chr14-64542534-G-A

Position:

• chr14-64542534-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021979.4(HSPA2):​c.1685G>A​(p.Arg562Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HSPA2 NM_021979.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.49

Genes affected

HSPA2 (HGNC:5235): (heat shock protein family A (Hsp70) member 2) Enables disordered domain specific binding activity; enzyme binding activity; and unfolded protein binding activity. Involved in negative regulation of inclusion body assembly and protein refolding. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06385735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA2	NM_021979.4	c.1685G>A	p.Arg562Lys	missense_variant	1/1	ENST00000247207.7	NP_068814.2
HSPA2	NM_001387931.1	c.1685G>A	p.Arg562Lys	missense_variant	2/2		NP_001374860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA2	ENST00000247207.7	c.1685G>A	p.Arg562Lys	missense_variant	1/1		NM_021979.4	ENSP00000247207	P1
HSPA2	ENST00000394709.2	c.1685G>A	p.Arg562Lys	missense_variant	2/2	1		ENSP00000378199	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 84

GnomAD4 genome Cov.: 31

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 03, 2023

The c.1685G>A (p.R562K) alteration is located in exon 1 (coding exon 1) of the HSPA2 gene. This alteration results from a G to A substitution at nucleotide position 1685, causing the arginine (R) at amino acid position 562 to be replaced by a lysine (K). 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	0.065
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.041	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.2	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.72	N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.073
MutPred		0.41		Gain of catalytic residue at L561 (P = 0.0039);Gain of catalytic residue at L561 (P = 0.0039);
MVP		0.31
ClinPred		0.80	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.23

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: chr14-65009252;