chr18-10787049-G-T

Variant names:

• chr18-10787049-G-T
• rs6505592
• NM_001378183.1:c.2305C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001378183.1(PIEZO2):​c.2305C>A​(p.Leu769Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. L769L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59
• Publications: 16 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056233436).

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.2305C>A	p.Leu769Met	missense	Exon 16 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.2305C>A	p.Leu769Met	missense	Exon 16 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.2305C>A	p.Leu769Met	missense	Exon 16 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.2305C>A	p.Leu769Met	missense	Exon 16 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.2305C>A	p.Leu769Met	missense	Exon 16 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.2305C>A	p.Leu769Met	missense	Exon 16 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000709 AC: 1 AN: 141046 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000966

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000145 AC: 2 AN: 1378412 Hom.: 0 Cov.: 41 AF XY: 0.00000147 AC XY: 1 AN XY: 680152

African (AFR) AF: 0.00 AC: 0 AN: 31222

American (AMR) AF: 0.00 AC: 0 AN: 34254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25050

East Asian (EAS) AF: 0.0000561 AC: 2 AN: 35650

South Asian (SAS) AF: 0.00 AC: 0 AN: 77894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075876

Other (OTH) AF: 0.00 AC: 0 AN: 57748

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 17529

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.0
DANN	Benign	0.49
DEOGEN2	Benign	0.0096	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		-1.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.029
Sift	Benign	0.27	T
Sift4G	Benign	0.45	T
Polyphen		0.21	B
Vest4		0.29
MutPred		0.28		Loss of methylation at K770 (P = 0.0445)
MVP		0.043
MPC		0.42
ClinPred		0.054	T
GERP RS		-5.9
Varity_R		0.066
gMVP		0.13
Mutation Taster		=79/21	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: rs6505592; hg19: chr18-10787047;