chr14-64542101-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_021979.4(HSPA2):ā€‹c.1252A>Gā€‹(p.Lys418Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000096 ( 0 hom. )

Consequence

HSPA2
NM_021979.4 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HSPA2NM_021979.4 linkuse as main transcriptc.1252A>G p.Lys418Glu missense_variant 1/1 ENST00000247207.7 NP_068814.2
HSPA2NM_001387931.1 linkuse as main transcriptc.1252A>G p.Lys418Glu missense_variant 2/2 NP_001374860.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HSPA2ENST00000247207.7 linkuse as main transcriptc.1252A>G p.Lys418Glu missense_variant 1/1 NM_021979.4 ENSP00000247207 P1
HSPA2ENST00000394709.2 linkuse as main transcriptc.1252A>G p.Lys418Glu missense_variant 2/21 ENSP00000378199 P1

Frequencies

GnomAD3 genomes
AF:
0.0000198
AC:
3
AN:
151866
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251224
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135874
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461520
Hom.:
0
Cov.:
86
AF XY:
0.0000138
AC XY:
10
AN XY:
727082
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000198
AC:
3
AN:
151866
Hom.:
0
Cov.:
31
AF XY:
0.0000270
AC XY:
2
AN XY:
74132
show subpopulations
Gnomad4 AFR
AF:
0.0000484
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000301
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 21, 2024The c.1252A>G (p.K418E) alteration is located in exon 1 (coding exon 1) of the HSPA2 gene. This alteration results from a A to G substitution at nucleotide position 1252, causing the lysine (K) at amino acid position 418 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
Uncertain
0.51
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.068
T;T
Eigen
Benign
-0.16
Eigen_PC
Benign
0.039
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Benign
0.028
D
MetaRNN
Uncertain
0.49
T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
-0.26
N;N
MutationTaster
Benign
0.97
D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-0.37
N;N
REVEL
Uncertain
0.37
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.48
T;T
Polyphen
0.0060
B;B
Vest4
0.73
MutPred
0.46
Loss of methylation at K418 (P = 7e-04);Loss of methylation at K418 (P = 7e-04);
MVP
0.46
ClinPred
0.90
D
GERP RS
4.1
Varity_R
0.65
gMVP
0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747324899; hg19: chr14-65008819; API