NM_001378183.1:c.6891C>G

Variant names:

• chr18-10696476-G-C
• rs16975188
• NM_001378183.1:c.6891C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001378183.1(PIEZO2):​c.6891C>G​(p.Ser2297Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S2297S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.393
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

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.6891C>G	p.Ser2297Arg	missense	Exon 46 of 56	NP_001365112.1
	PIEZO2	NM_001410871.1		c.6627C>G	p.Ser2209Arg	missense	Exon 44 of 54	NP_001397800.1
	PIEZO2	NM_022068.4		c.6552C>G	p.Ser2184Arg	missense	Exon 42 of 52	NP_071351.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.6891C>G	p.Ser2297Arg	missense	Exon 46 of 56	ENSP00000501957.1
	PIEZO2	ENST00000503781.7	TSL:1	c.6552C>G	p.Ser2184Arg	missense	Exon 42 of 52	ENSP00000421377.3
	PIEZO2	ENST00000580640.5	TSL:5	c.6627C>G	p.Ser2209Arg	missense	Exon 44 of 54	ENSP00000463094.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	10
DANN	Benign	0.93
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.39
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.56
Sift	Benign	0.81	T
Sift4G	Benign	0.55	T
Vest4		0.85
MutPred		0.58		Gain of methylation at S2184 (P = 0.0229)
MVP		0.29
MPC		0.49
ClinPred		0.50	T
GERP RS		-3.3
Varity_R		0.16
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs16975188; hg19: chr18-10696474;