21-31924613-A-G

Position:

• chr21-31924613-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014586.2(HUNK):​c.407A>G​(p.Tyr136Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HUNK NM_014586.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.97

Genes affected

HUNK (HGNC:13326): (hormonally up-regulated Neu-associated kinase) Predicted to enable protein serine/threonine kinase activity. Predicted to be involved in intracellular signal transduction and protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUNK	NM_014586.2	c.407A>G	p.Tyr136Cys	missense_variant	2/11	ENST00000270112.7	NP_055401.1
HUNK	XM_011529537.3	c.407A>G	p.Tyr136Cys	missense_variant	2/10		XP_011527839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUNK	ENST00000270112.7	c.407A>G	p.Tyr136Cys	missense_variant	2/11	1	NM_014586.2	ENSP00000270112	P1
HUNK	ENST00000430354.1	c.62A>G	p.Tyr21Cys	missense_variant	1/4	3		ENSP00000411860

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.407A>G (p.Y136C) alteration is located in exon 2 (coding exon 2) of the HUNK gene. This alteration results from a A to G substitution at nucleotide position 407, causing the tyrosine (Y) at amino acid position 136 to be replaced by a cysteine (C). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.3	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.58		Loss of phosphorylation at Y136 (P = 0.0637);.;
MVP		0.88
MPC		2.2
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.80
gMVP		0.86

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-33296925;