NM_004304.5:c.2772T>G

Variant names:

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

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

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.

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

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.2772T>G	p.Gly924Gly	synonymous	Exon 16 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000618119.4	TSL:5	c.1641T>G	p.Gly547Gly	synonymous	Exon 15 of 28	ENSP00000482733.1	A0A087WZL3

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Neuroblastoma, susceptibility to, 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;