NM_004304.5:c.1464C>T

Variant names:

• chr2-29320833-G-A
• rs56165377
• NM_004304.5:c.1464C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004304.5(ALK):​c.1464C>T​(p.Gly488Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.009 in 1,614,186 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0093 (95 hom.)
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.37

Genes affected

ALK (HGNC:427): (ALK receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]

ENSG00000286963 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 2-29320833-G-A is Benign according to our data. Variant chr2-29320833-G-A is described in ClinVar as [Benign]. Clinvar id is 259265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29320833-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00606 (923/152320) while in subpopulation AMR AF= 0.00947 (145/15306). AF 95% confidence interval is 0.00833. There are 2 homozygotes in gnomad4. There are 432 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 923 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.1464C>T	p.Gly488Gly	synonymous_variant	Exon 7 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.2391C>T		non_coding_transcript_exon_variant	Exon 7 of 18
LOC101929386	XR_007086263.1	n.376+860G>A		intron_variant	Intron 2 of 4
LOC101929386	XR_939920.3	n.89-646G>A		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.1464C>T	p.Gly488Gly	synonymous_variant	Exon 7 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.333C>T	p.Gly111Gly	synonymous_variant	Exon 6 of 28	5		ENSP00000482733.1
ENSG00000286963	ENST00000655343.1	n.220+860G>A		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 923 AN: 152202 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00949

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00892

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00598 AC: 1503 AN: 251410 Hom.: 12 AF XY: 0.00599 AC XY: 814 AN XY: 135864

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00561

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.00943

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00930 AC: 13600 AN: 1461866 Hom.: 95 Cov.: 36 AF XY: 0.00907 AC XY: 6599 AN XY: 727236

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00610

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00505

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00881

GnomAD4 genome AF: 0.00606 AC: 923 AN: 152320 Hom.: 2 Cov.: 33 AF XY: 0.00580 AC XY: 432 AN XY: 74480

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00947

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00892

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00730 Hom.: 1

Bravo AF: 0.00654

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0114

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:3

Sep 20, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 13, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALK: BP4, BS1, BS2; ENSG00000286963: BS1, BS2 -

Aug 24, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ALK c.1464C>T (p.Gly488Gly) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 681/121400 control chromosomes (5 homozygotes) at a frequency of 0.0056096, which is approximately 13463 times the estimated maximal expected allele frequency of a pathogenic ALK variant (0.0000004), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign. -

Hereditary cancer-predisposing syndrome Benign:2

Feb 24, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 06, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56165377; hg19: chr2-29543699; COSMIC: COSV66555770; COSMIC: COSV66555770;