rs998757704

Positions:

• chr18-10705418-C-A
• chr18-10705418-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001378183.1(PIEZO2):​c.5917G>T​(p.Asp1973Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1973N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.5917G>T	p.Asp1973Tyr	missense_variant	41/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.5917G>T	p.Asp1973Tyr	missense_variant	41/56		NM_001378183.1
	ENST00000584167.1	n.112C>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Benign	0.87
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.8	L;.;.;L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D;.;.;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.010	D;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;.
Vest4		0.53
MutPred		0.28		Gain of phosphorylation at D1860 (P = 0.0137);.;.;Gain of phosphorylation at D1860 (P = 0.0137);.;
MVP		0.37
MPC		1.0
ClinPred		0.79	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.58

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: rs998757704; hg19: chr18-10705416;