chr14-64542028-C-G

Position:

• chr14-64542028-C-G

Variant summary

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

The NM_021979.4(HSPA2):​c.1179C>G​(p.Asp393Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.638

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 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	Protein	UniProt
HSPA2	NM_021979.4	c.1179C>G	p.Asp393Glu	missense_variant	1/1	ENST00000247207.7	NP_068814.2
HSPA2	NM_001387931.1	c.1179C>G	p.Asp393Glu	missense_variant	2/2		NP_001374860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA2	ENST00000247207.7	c.1179C>G	p.Asp393Glu	missense_variant	1/1		NM_021979.4	ENSP00000247207	P1
HSPA2	ENST00000394709.2	c.1179C>G	p.Asp393Glu	missense_variant	2/2	1		ENSP00000378199	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 85

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

Nov 21, 2022

The c.1179C>G (p.D393E) alteration is located in exon 1 (coding exon 1) of the HSPA2 gene. This alteration results from a C to G substitution at nucleotide position 1179, causing the aspartic acid (D) at amino acid position 393 to be replaced by a glutamic acid (E). 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	0.65
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.89	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.086	T;T
Polyphen		0.053	B;B
Vest4		0.73
MutPred		0.68		Gain of catalytic residue at D398 (P = 0.0809);Gain of catalytic residue at D398 (P = 0.0809);
MVP		0.31
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.85
gMVP		0.83

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: chr14-65008746;