2-29192926-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004304.5(ALK):c.*298C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 453,082 control chromosomes in the GnomAD database, including 224,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.99 (74874 hom., cov: 32)
  • Exomes 𝑓: 1.0 (149954 hom.)
• Consequence: ALK NM_004304.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.258

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]

CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-29192926-G-A is Benign according to our data. Variant chr2-29192926-G-A is described in ClinVar as [Benign]. Clinvar id is 335677.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.*298C>T		3_prime_UTR_variant	29/29	ENST00000389048.8
ALK	NM_001353765.2	c.*298C>T		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.*298C>T		3_prime_UTR_variant	29/29	1	NM_004304.5	P1

Frequencies

GnomAD3 genomes AF: 0.991 AC: 150915 AN: 152228 Hom.: 74816 Cov.: 32

Gnomad AFR AF: 0.970

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.994

GnomAD4 exome AF: 0.999 AC: 300311 AN: 300736 Hom.: 149954 Cov.: 2 AF XY: 0.999 AC XY: 156875 AN XY: 157056

Gnomad4 AFR exome AF: 0.969

Gnomad4 AMR exome AF: 0.999

Gnomad4 ASJ exome AF: 0.996

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.998

GnomAD4 genome AF: 0.991 AC: 151032 AN: 152346 Hom.: 74874 Cov.: 32 AF XY: 0.992 AC XY: 73898 AN XY: 74498

Gnomad4 AFR AF: 0.970

Gnomad4 AMR AF: 0.999

Gnomad4 ASJ AF: 0.996

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.994

Alfa AF: 0.998 Hom.: 77390

Bravo AF: 0.990

Asia WGS AF: 1.00 AC: 3476 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	6.4
Dann	Benign	0.22

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: rs1728828; hg19: chr2-29415792;