2-29220751-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004304.5(ALK):c.3600G>A(p.Ala1200=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1200A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.88

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-29220751-C-T is Benign according to our data. Variant chr2-29220751-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 239826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.88 with no splicing effect.
• BS2: High AC in GnomAd at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.3600G>A	p.Ala1200=	synonymous_variant	23/29	ENST00000389048.8
ALK	NM_001353765.2	c.396G>A	p.Ala132=	synonymous_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.3600G>A	p.Ala1200=	synonymous_variant	23/29	1	NM_004304.5	P1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 250662 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135502

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000112 AC: 163 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.000118 AC XY: 86 AN XY: 727122

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000881

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74466

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000457

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 14, 2016	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. -

Neuroblastoma, susceptibility to, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

ALK-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

ALK: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.0050
Dann	Benign	0.72

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: rs56247462; hg19: chr2-29443617;