18-10696476-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001378183.1(PIEZO2):​c.6891C>G​(p.Ser2297Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2297S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

PIEZO2
NM_001378183.1 missense

Scores

5
5
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.393
Variant links:
Genes affected
PIEZO2 (HGNC:26270): (piezo type mechanosensitive ion channel component 2) The protein encoded by this gene contains more than thirty transmembrane domains and likely functions as part of mechanically-activated (MA) cation channels. These channels serve to connect mechanical forces to biological signals. The encoded protein quickly adapts MA currents in somatosensory neurons. Defects in this gene are a cause of type 5 distal arthrogryposis. Several alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Feb 2014]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PIEZO2NM_001378183.1 linkc.6891C>G p.Ser2297Arg missense_variant Exon 46 of 56 ENST00000674853.1 NP_001365112.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PIEZO2ENST00000674853.1 linkc.6891C>G p.Ser2297Arg missense_variant Exon 46 of 56 NM_001378183.1 ENSP00000501957.1 A0A2H4UKA7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461824
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
727220
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
CADD
Benign
10
DANN
Benign
0.93
DEOGEN2
Benign
0.0045
.;T;.;T
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.65
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.86
D;D;D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.91
D;D;D;D
MetaSVM
Uncertain
-0.17
T
MutationAssessor
Benign
1.3
L;.;.;L
PrimateAI
Pathogenic
0.79
T
PROVEAN
Benign
-0.66
N;.;.;.
REVEL
Uncertain
0.56
Sift
Benign
0.81
T;.;.;.
Sift4G
Benign
0.55
T;T;T;T
Vest4
0.85
MutPred
0.58
Gain of methylation at S2184 (P = 0.0229);.;.;Gain of methylation at S2184 (P = 0.0229);
MVP
0.29
MPC
0.49
ClinPred
0.50
T
GERP RS
-3.3
Varity_R
0.16
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: chr18-10696474; API