20-32052455-G-A

Variant names:

• chr20-32052455-G-A
• rs968047363
• NM_002110.5:c.31G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002110.5(HCK):​c.31G>A​(p.Gly11Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000269 in 1,116,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HCK NM_002110.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63

Genes affected

HCK (HGNC:4840): (HCK proto-oncogene, Src family tyrosine kinase) The protein encoded by this gene is a member of the Src family of tyrosine kinases. This protein is primarily hemopoietic, particularly in cells of the myeloid and B-lymphoid lineages. It may help couple the Fc receptor to the activation of the respiratory burst. In addition, it may play a role in neutrophil migration and in the degranulation of neutrophils. Multiple isoforms with different subcellular distributions are produced due to both alternative splicing and the use of alternative translation initiation codons, including a non-AUG (CUG) codon. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28415313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCK	NM_002110.5	c.31G>A	p.Gly11Ser	missense_variant	Exon 1 of 13	ENST00000375852.5	NP_002101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCK	ENST00000375852.5	c.31G>A	p.Gly11Ser	missense_variant	Exon 1 of 13	1	NM_002110.5	ENSP00000365012.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000269 AC: 3 AN: 1116334 Hom.: 0 Cov.: 30 AF XY: 0.00000377 AC XY: 2 AN XY: 530860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000322

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31G>A (p.G11S) alteration is located in exon 1 (coding exon 1) of the HCK gene. This alteration results from a G to A substitution at nucleotide position 31, causing the glycine (G) at amino acid position 11 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0056	T;T;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.61	T;T;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.9	.;.;M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.18	N;N;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.041	D;D;.;.
Sift4G	Benign	0.13	T;T;T;.
Polyphen		1.0	.;.;D;.
Vest4		0.49
MutPred		0.095		Gain of phosphorylation at G11 (P = 0.0063);Gain of phosphorylation at G11 (P = 0.0063);Gain of phosphorylation at G11 (P = 0.0063);Gain of phosphorylation at G11 (P = 0.0063);
MVP		0.82
ClinPred		0.64	D
GERP RS		3.0
Varity_R		0.085
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs968047363; hg19: chr20-30640258;