chr18-11066135-G-A

Position:

• chr18-11066135-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001378183.1(PIEZO2):​c.152C>T​(p.Thr51Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 1,531,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 9.43

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27508387).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.152C>T	p.Thr51Met	missense_variant	2/56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.152C>T	p.Thr51Met	missense_variant	2/56		NM_001378183.1	ENSP00000501957

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000779

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000303 AC: 43 AN: 141828 Hom.: 0 AF XY: 0.000382 AC XY: 29 AN XY: 75848

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.0000407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000881

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000560 AC: 772 AN: 1379592 Hom.: 0 Cov.: 29 AF XY: 0.000556 AC XY: 379 AN XY: 681126

Gnomad4 AFR exome AF: 0.0000953

Gnomad4 AMR exome AF: 0.0000841

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.0000572

Gnomad4 NFE exome AF: 0.000695

Gnomad4 OTH exome AF: 0.000191

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74314

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000395 Hom.: 0

Bravo AF: 0.000423

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.000234 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.152C>T (p.T51M) alteration is located in exon 2 (coding exon 2) of the PIEZO2 gene. This alteration results from a C to T substitution at nucleotide position 152, causing the threonine (T) at amino acid position 51 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Arthrogryposis, distal, with impaired proprioception and touch Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Benign	0.60
DEOGEN2	Benign	0.020	.;.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.020	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D;.;.
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.58
MVP		0.16
MPC		1.0
ClinPred		0.12	T
GERP RS		5.8
Varity_R		0.067
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs371432372; hg19: chr18-11066134; COSMIC: COSV57431799;