21-31924757-A-T

Position:

• chr21-31924757-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014586.2(HUNK):​c.551A>T​(p.His184Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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: 8.91

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUNK	NM_014586.2	c.551A>T	p.His184Leu	missense_variant	2/11	ENST00000270112.7	NP_055401.1
HUNK	XM_011529537.3	c.551A>T	p.His184Leu	missense_variant	2/10		XP_011527839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUNK	ENST00000270112.7	c.551A>T	p.His184Leu	missense_variant	2/11	1	NM_014586.2	ENSP00000270112	P1
HUNK	ENST00000430354.1	c.206A>T	p.His69Leu	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

Oct 27, 2022

The c.551A>T (p.H184L) alteration is located in exon 2 (coding exon 2) of the HUNK gene. This alteration results from a A to T substitution at nucleotide position 551, causing the histidine (H) at amino acid position 184 to be replaced by a leucine (L). 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	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	4.0	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-10	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.93		Gain of ubiquitination at K188 (P = 0.0941);.;
MVP		0.91
MPC		2.2
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-33297069;