rs761724656

chr2-29318404-T-Achr2-29318404-T-Cchr2-29318404-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004304.5(ALK):c.1547A>T(p.Asp516Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D516G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 missense, splice_region
• Scores: Splicing: ADA: 0.0004463
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.496

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.1547A>T	p.Asp516Val	missense_variant, splice_region_variant	8/29	ENST00000389048.8
ALK	XR_001738688.3	n.2474A>T		splice_region_variant, non_coding_transcript_exon_variant	8/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.1547A>T	p.Asp516Val	missense_variant, splice_region_variant	8/29	1	NM_004304.5	P1
ALK	ENST00000618119.4	c.416A>T	p.Asp139Val	missense_variant, splice_region_variant	7/28	5
ALK	ENST00000498037.1	n.102A>T		splice_region_variant, non_coding_transcript_exon_variant	2/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.099	T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.093
Sift	Benign	0.050	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.0020	B;.
Vest4		0.57
MutPred		0.62		Loss of disorder (P = 0.0174);.;
MVP		0.35
MPC		0.45
ClinPred		0.35	T
GERP RS		3.2
Varity_R		0.10
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00045
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-29541270;