rs113682091

Variant names:

• chr18-10699131-G-T
• rs113682091
• NM_001378183.1:c.6488C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-10699131-G-T
• chr18-10699131-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378183.1(PIEZO2):​c.6488C>A​(p.Ala2163Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0798 in 1,537,064 control chromosomes in the GnomAD database, including 6,147 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2163T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1370 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4777 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.37
• Publications: 5 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• arthrogryposis, distal, with impaired proprioception and touch

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• connective tissue disorder

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Marden-Walker syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018732846).
• BP6: Variant 18-10699131-G-T is Benign according to our data. Variant chr18-10699131-G-T is described in ClinVar as Benign. ClinVar VariationId is 261521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	NM_001378183.1	MANE Select	c.6488C>A	p.Ala2163Asp	missense	Exon 44 of 56	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.6224C>A	p.Ala2075Asp	missense	Exon 42 of 54	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.6149C>A	p.Ala2050Asp	missense	Exon 40 of 52	NP_071351.2	Q9H5I5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.6488C>A	p.Ala2163Asp	missense	Exon 44 of 56	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.6149C>A	p.Ala2050Asp	missense	Exon 40 of 52	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.6224C>A	p.Ala2075Asp	missense	Exon 42 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16655 AN: 152036 Hom.: 1356 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0667

Gnomad ASJ AF: 0.0674

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0613

Gnomad FIN AF: 0.0611

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.0915

GnomAD2 exomes AF: 0.0697 AC: 9874 AN: 141580 AF XY: 0.0683

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.0508

Gnomad ASJ exome AF: 0.0645

Gnomad EAS exome AF: 0.00141

Gnomad FIN exome AF: 0.0554

Gnomad NFE exome AF: 0.0708

Gnomad OTH exome AF: 0.0612

GnomAD4 exome AF: 0.0766 AC: 106025 AN: 1384910 Hom.: 4777 Cov.: 32 AF XY: 0.0757 AC XY: 51723 AN XY: 683384

African (AFR) AF: 0.239 AC: 7565 AN: 31594

American (AMR) AF: 0.0562 AC: 2005 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.0641 AC: 1615 AN: 25182

East Asian (EAS) AF: 0.000784 AC: 28 AN: 35734

South Asian (SAS) AF: 0.0681 AC: 5395 AN: 79234

European-Finnish (FIN) AF: 0.0561 AC: 1965 AN: 34998

Middle Eastern (MID) AF: 0.0400 AC: 228 AN: 5694

European-Non Finnish (NFE) AF: 0.0768 AC: 82824 AN: 1078860

Other (OTH) AF: 0.0760 AC: 4400 AN: 57914

GnomAD4 genome AF: 0.110 AC: 16686 AN: 152154 Hom.: 1370 Cov.: 32 AF XY: 0.107 AC XY: 7935 AN XY: 74372

African (AFR) AF: 0.230 AC: 9555 AN: 41472

American (AMR) AF: 0.0664 AC: 1015 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0674 AC: 234 AN: 3470

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5180

South Asian (SAS) AF: 0.0612 AC: 295 AN: 4822

European-Finnish (FIN) AF: 0.0611 AC: 647 AN: 10594

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0694 AC: 4719 AN: 68010

Other (OTH) AF: 0.0896 AC: 189 AN: 2110

Alfa AF: 0.0799 Hom.: 1209

Bravo AF: 0.117

TwinsUK AF: 0.0825 AC: 306

ALSPAC AF: 0.0812 AC: 313

ExAC AF: 0.0751 AC: 1612

Asia WGS AF: 0.0490 AC: 171 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Arthrogryposis, distal, with impaired proprioception and touch (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.7
DANN	Benign	0.69
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.6	N
PhyloP100		1.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.13
Sift	Benign	0.78	T
Sift4G	Benign	0.68	T
Vest4		0.085
MPC		0.45
ClinPred		0.0029	T
GERP RS		5.8
Varity_R		0.036
gMVP		0.41
Mutation Taster		=96/4	polymorphism (auto)

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: rs113682091; hg19: chr18-10699129; COSMIC: COSV53290641;