rs1555638058

Positions:

• chr18-10752640-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001378183.1(PIEZO2):​c.4163T>C​(p.Leu1388Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant 18-10752640-A-G is Pathogenic according to our data. Variant chr18-10752640-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520914.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIEZO2	NM_001378183.1	c.4163T>C	p.Leu1388Pro	missense_variant	28/56	ENST00000674853.1	NP_001365112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIEZO2	ENST00000674853.1	c.4163T>C	p.Leu1388Pro	missense_variant	28/56		NM_001378183.1	ENSP00000501957.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384760 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 683278

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	.;T;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.0	M;.;.;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.3	D;.;.;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.021	D;D;D;D
Vest4		0.97
MutPred		0.66		Loss of stability (P = 0.0123);.;.;Loss of stability (P = 0.0123);
MVP		0.33
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.99

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: rs1555638058; hg19: chr18-10752638;