chr18-10979657-T-G

Variant names:

• chr18-10979657-T-G
• rs145948919
• NM_001378183.1:c.164A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378183.1(PIEZO2):​c.164A>C​(p.His55Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0162 in 1,533,854 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (27 hom., cov: 32)
  • Exomes 𝑓: 0.017 (226 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.49
• Publications: 5 publications found

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]

PIEZO2 Gene-Disease associations (from GenCC):

• Gordon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• arthrogryposis, distal, with impaired proprioception and touch

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics
• arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• connective tissue disorder

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Marden-Walker syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009269655).
• BP6: Variant 18-10979657-T-G is Benign according to our data. Variant chr18-10979657-T-G is described in ClinVar as Benign. ClinVar VariationId is 261499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0127 (1937/152302) while in subpopulation NFE AF = 0.0202 (1377/68036). AF 95% confidence interval is 0.0194. There are 27 homozygotes in GnomAd4. There are 912 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378183.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	NM_001378183.1	MANE Select	c.164A>C	p.His55Pro	missense	Exon 3 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.164A>C	p.His55Pro	missense	Exon 3 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.164A>C	p.His55Pro	missense	Exon 3 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.164A>C	p.His55Pro	missense	Exon 3 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.164A>C	p.His55Pro	missense	Exon 3 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.164A>C	p.His55Pro	missense	Exon 3 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1937 AN: 152184 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.0112 AC: 1575 AN: 140684 AF XY: 0.0102

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00540

Gnomad EAS exome AF: 0.0000947

Gnomad FIN exome AF: 0.00993

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.00954

GnomAD4 exome AF: 0.0166 AC: 22886 AN: 1381552 Hom.: 226 Cov.: 30 AF XY: 0.0160 AC XY: 10919 AN XY: 681744

African (AFR) AF: 0.00289 AC: 91 AN: 31520

American (AMR) AF: 0.00992 AC: 352 AN: 35476

Ashkenazi Jewish (ASJ) AF: 0.00571 AC: 143 AN: 25056

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35690

South Asian (SAS) AF: 0.00109 AC: 86 AN: 78862

European-Finnish (FIN) AF: 0.00794 AC: 277 AN: 34904

Middle Eastern (MID) AF: 0.00229 AC: 13 AN: 5682

European-Non Finnish (NFE) AF: 0.0197 AC: 21190 AN: 1076616

Other (OTH) AF: 0.0127 AC: 733 AN: 57746

GnomAD4 genome AF: 0.0127 AC: 1937 AN: 152302 Hom.: 27 Cov.: 32 AF XY: 0.0122 AC XY: 912 AN XY: 74474

African (AFR) AF: 0.00366 AC: 152 AN: 41556

American (AMR) AF: 0.0133 AC: 204 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0202 AC: 1377 AN: 68036

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.0172 Hom.: 42

Bravo AF: 0.0125

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00578 AC: 8

ESP6500EA AF: 0.0176 AC: 56

ExAC AF: 0.00696 AC: 144

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Benign	0.73
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.024	D
Vest4		0.76
MPC		1.3
ClinPred		0.017	T
GERP RS		6.1
Varity_R		0.52
gMVP		0.72
Mutation Taster		=80/20	polymorphism

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: rs145948919; hg19: chr18-10979655; COSMIC: COSV100126124;