rs577065337

chr18-10704429-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001378183.1(PIEZO2):c.6223C>T(p.Arg2075Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000178 in 1,537,214 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 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.18

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027192831).
• BP6: Variant 18-10704429-G-A is Benign according to our data. Variant chr18-10704429-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547940.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.6223C>T	p.Arg2075Cys	missense_variant	42/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.6223C>T	p.Arg2075Cys	missense_variant	42/56		NM_001378183.1
	ENST00000584167.1	n.37+96G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000233 AC: 33 AN: 141708 Hom.: 0 AF XY: 0.000171 AC XY: 13 AN XY: 75820

Gnomad AFR exome AF: 0.00199

Gnomad AMR exome AF: 0.000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 183 AN: 1384936 Hom.: 0 Cov.: 30 AF XY: 0.000126 AC XY: 86 AN XY: 683394

Gnomad4 AFR exome AF: 0.00193

Gnomad4 AMR exome AF: 0.000308

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.000143

Gnomad4 NFE exome AF: 0.0000779

Gnomad4 OTH exome AF: 0.000311

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74458

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.000586

ExAC AF: 0.000181 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.5884C>T (p.R1962C) alteration is located in exon 38 (coding exon 38) of the PIEZO2 gene. This alteration results from a C to T substitution at nucleotide position 5884, causing the arginine (R) at amino acid position 1962 to be replaced by a cysteine (C). 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

Mar 10, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	26
Dann	Benign	0.97
Eigen	Benign	0.13
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.027	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D;.;.;.
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.49
MutPred		0.68		Loss of MoRF binding (P = 0.0635);.;.;Loss of MoRF binding (P = 0.0635);
MVP		0.043
MPC		1.0
ClinPred		0.16	T
GERP RS		1.8
Varity_R		0.27
gMVP		0.72

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

Other links and lift over

dbSNP: rs577065337; hg19: chr18-10704427;