rs749286400

Variant names:

• chr2-29228927-A-C
• rs749286400
• NM_004304.5:c.2772T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-29228927-A-C
• chr2-29228927-A-G
• chr2-29228927-A-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_004304.5(ALK):​c.2772T>G​(p.Gly924Gly) 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:3
• Conservation: PhyloP100: 2.73
• Publications: 3 publications found

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]

ALK Gene-Disease associations (from GenCC):

• neuroblastoma, susceptibility to, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 239814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.73 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.2772T>G	p.Gly924Gly	synonymous_variant	Exon 16 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.3668+31T>G		intron_variant	Intron 16 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.2772T>G	p.Gly924Gly	synonymous_variant	Exon 16 of 29	1	NM_004304.5	ENSP00000373700.3
ALK	ENST00000618119.4	c.1641T>G	p.Gly547Gly	synonymous_variant	Exon 15 of 28	5		ENSP00000482733.1

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 2927 AN: 63884 Hom.: 0 Cov.: 14

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

GnomAD2 exomes AF: 0.0745 AC: 13727 AN: 184150 AF XY: 0.0703

Gnomad AFR exome AF: 0.0592

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.0850

Gnomad EAS exome AF: 0.138

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0514

Gnomad OTH exome AF: 0.118

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0952 AC: 1176 AN: 12352

American (AMR) AF: 0.128 AC: 3050 AN: 23892

Ashkenazi Jewish (ASJ) AF: 0.0811 AC: 977 AN: 12050

East Asian (EAS) AF: 0.0982 AC: 2145 AN: 21848

South Asian (SAS) AF: 0.121 AC: 4070 AN: 33666

European-Finnish (FIN) AF: 0.0414 AC: 1265 AN: 30592

Middle Eastern (MID) AF: 0.0487 AC: 143 AN: 2938

European-Non Finnish (NFE) AF: 0.0862 AC: 26868 AN: 311736

Other (OTH) AF: 0.0875 AC: 1882 AN: 21512

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0446 AC: 744 AN: 16666

American (AMR) AF: 0.0355 AC: 229 AN: 6442

Ashkenazi Jewish (ASJ) AF: 0.0508 AC: 78 AN: 1534

East Asian (EAS) AF: 0.0144 AC: 32 AN: 2228

South Asian (SAS) AF: 0.0333 AC: 58 AN: 1740

European-Finnish (FIN) AF: 0.0539 AC: 236 AN: 4376

Middle Eastern (MID) AF: 0.0259 AC: 3 AN: 116

European-Non Finnish (NFE) AF: 0.0502 AC: 1488 AN: 29616

Other (OTH) AF: 0.0576 AC: 46 AN: 798

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.149 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Benign:1

Jan 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Benign:1

Mar 01, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		2.7
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs749286400; hg19: chr2-29451793;