14-64541742-C-G

Variant names:

• chr14-64541742-C-G
• rs370673877
• NM_021979.4:c.893C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021979.4(HSPA2):​c.893C>G​(p.Thr298Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T298M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HSPA2 NM_021979.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA2	NM_021979.4	c.893C>G	p.Thr298Arg	missense_variant	Exon 1 of 1	ENST00000247207.7	NP_068814.2
HSPA2	NM_001387931.1	c.893C>G	p.Thr298Arg	missense_variant	Exon 2 of 2		NP_001374860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA2	ENST00000247207.7	c.893C>G	p.Thr298Arg	missense_variant	Exon 1 of 1	6	NM_021979.4	ENSP00000247207.6
HSPA2	ENST00000394709.2	c.893C>G	p.Thr298Arg	missense_variant	Exon 2 of 2	1		ENSP00000378199.1
HSPA2	ENST00000554883.1	n.*167C>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245020 AF XY: 0.00000750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000912

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 86

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.66		Gain of catalytic residue at V294 (P = 0.0371);Gain of catalytic residue at V294 (P = 0.0371);
MVP		0.46
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.96
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs370673877; hg19: chr14-65008460;