rs749286400

chr2-29228927-A-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_004304.5(ALK):c.2772T>G(p.Gly924=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (0 hom., cov: 14)
  • Exomes 𝑓: 0.088 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.73

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-29228927-A-C is Benign according to our data. Variant chr2-29228927-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 239814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-29228927-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.73 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.2772T>G	p.Gly924=	synonymous_variant	16/29	ENST00000389048.8
ALK	XR_001738688.3	n.3668+31T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.2772T>G	p.Gly924=	synonymous_variant	16/29	1	NM_004304.5	P1
ALK	ENST00000618119.4	c.1641T>G	p.Gly547=	synonymous_variant	15/28	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2927 AN: 63884 Hom.: 0 Cov.: 14 FAILED QC

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.0325

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.0508

Gnomad EAS AF: 0.0139

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.0539

Gnomad MID AF: 0.0246

Gnomad NFE AF: 0.0502

Gnomad OTH AF: 0.0576

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0883 AC: 41576 AN: 470586 Hom.: 0 Cov.: 15 AF XY: 0.0883 AC XY: 21651 AN XY: 245286

Gnomad4 AFR exome AF: 0.0952

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.0811

Gnomad4 EAS exome AF: 0.0982

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.0414

Gnomad4 NFE exome AF: 0.0862

Gnomad4 OTH exome AF: 0.0875

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0458 AC: 2927 AN: 63916 Hom.: 0 Cov.: 14 AF XY: 0.0424 AC XY: 1310 AN XY: 30918

Gnomad4 AFR AF: 0.0446

Gnomad4 AMR AF: 0.0355

Gnomad4 ASJ AF: 0.0508

Gnomad4 EAS AF: 0.0144

Gnomad4 SAS AF: 0.0333

Gnomad4 FIN AF: 0.0539

Gnomad4 NFE AF: 0.0502

Gnomad4 OTH AF: 0.0576

Alfa AF: 0.149 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2022

This alteration is classified as likely 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	-0.46
Cadd	Benign	13
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs749286400; hg19: chr2-29451793;