2-29228927-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_004304.5(ALK):​c.2772T>A​(p.Gly924Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G924G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 14)
  • Exomes 𝑓: 0.000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• 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>A	p.Gly924Gly	synonymous_variant	Exon 16 of 29	ENST00000389048.8	NP_004295.2
ALK	XR_001738688.3	n.3668+31T>A		intron_variant	Intron 16 of 17

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 73872 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 8 AN: 501912 Hom.: 0 Cov.: 15 AF XY: 0.0000191 AC XY: 5 AN XY: 261458

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

African (AFR) AF: 0.00 AC: 0 AN: 13344

American (AMR) AF: 0.00 AC: 0 AN: 26726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13064

East Asian (EAS) AF: 0.00 AC: 0 AN: 22640

South Asian (SAS) AF: 0.0000837 AC: 3 AN: 35854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3056

European-Non Finnish (NFE) AF: 0.0000151 AC: 5 AN: 331846

Other (OTH) AF: 0.00 AC: 0 AN: 22922

⚠️ 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: AC0 AF: 0.00 AC: 0 AN: 73872 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 35264

African (AFR) AF: 0.00 AC: 0 AN: 19160

American (AMR) AF: 0.00 AC: 0 AN: 7286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1796

East Asian (EAS) AF: 0.00 AC: 0 AN: 2378

South Asian (SAS) AF: 0.00 AC: 0 AN: 1852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 35052

Other (OTH) AF: 0.00 AC: 0 AN: 932

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.72
PhyloP100		2.7
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;