NM_004304.5:c.2772T>C

Variant names:

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

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>C​(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: not found (cov: 14)
  • Exomes 𝑓: 0.000012 (0 hom.)
• 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=-0.37).
• BP7: Synonymous conserved (PhyloP=2.73 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004304.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.2772T>C	p.Gly924Gly	synonymous	Exon 16 of 29	NP_004295.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.2772T>C	p.Gly924Gly	synonymous	Exon 16 of 29	ENSP00000373700.3
	ALK	ENST00000618119.4	TSL:5	c.1641T>C	p.Gly547Gly	synonymous	Exon 15 of 28	ENSP00000482733.1

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome AF: 0.0000120 AC: 6 AN: 501906 Hom.: 0 Cov.: 15 AF XY: 0.0000115 AC XY: 3 AN XY: 261460

⚠️ 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: 0.00 AC: 0 AN: 35858

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: 331836

Other (OTH) AF: 0.0000436 AC: 1 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 Cov.: 14

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		2.7
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs749286400; hg19: chr2-29451793;