rs76488076

Variant names:

• chr18-10787128-A-C
• NM_001378183.1:c.2226T>G

Your query was ambiguous. Multiple possible variants found:

• chr18-10787128-A-C
• chr18-10787128-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378183.1(PIEZO2):​c.2226T>G​(p.Ile742Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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. I742I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00600

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22259504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.2226T>G	p.Ile742Met	missense_variant	Exon 16 of 56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.2226T>G	p.Ile742Met	missense_variant	Exon 16 of 56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383478 Hom.: 0 Cov.: 35 AF XY: 0.00000146 AC XY: 1 AN XY: 682654

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: 9.28e-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	Benign	0.11
BayesDel_addAF	Benign	0.0044	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.020	.;T;.;T
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.6	L;.;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.47	N;.;.;.
REVEL	Benign	0.071
Sift	Benign	0.057	T;.;.;.
Sift4G	Uncertain	0.013	D;D;D;D
Vest4		0.32
MutPred		0.51		Loss of catalytic residue at I742 (P = 0.0041);.;Loss of catalytic residue at I742 (P = 0.0041);Loss of catalytic residue at I742 (P = 0.0041);
MVP		0.18
MPC		0.33
ClinPred		0.049	T
GERP RS		0.27
Varity_R		0.067
gMVP		0.24

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: chr18-10787126;