rs8096037

Variant names:

• chr18-10748605-A-T
• rs8096037
• NM_001378183.1:c.4290T>A

Your query was ambiguous. Multiple possible variants found:

• chr18-10748605-A-T
• chr18-10748605-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378183.1(PIEZO2):​c.4290T>A​(p.Leu1430Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,524,030 control chromosomes in the GnomAD database, including 242,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32696 hom., cov: 32)
  • Exomes 𝑓: 0.55 (209711 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.27
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-10748605-A-T is Benign according to our data. Variant chr18-10748605-A-T is described in ClinVar as Benign. ClinVar VariationId is 261509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.883 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.4290T>A	p.Leu1430Leu	synonymous	Exon 30 of 56	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.4290T>A	p.Leu1430Leu	synonymous	Exon 30 of 54	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.4215T>A	p.Leu1405Leu	synonymous	Exon 28 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.4290T>A	p.Leu1430Leu	synonymous	Exon 30 of 56	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.4215T>A	p.Leu1405Leu	synonymous	Exon 28 of 52	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.4290T>A	p.Leu1430Leu	synonymous	Exon 30 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96295 AN: 151974 Hom.: 32645 Cov.: 32

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.603

GnomAD2 exomes AF: 0.548 AC: 71089 AN: 129772 AF XY: 0.544

Gnomad AFR exome AF: 0.902

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.706

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.555

Gnomad OTH exome AF: 0.548

GnomAD4 exome AF: 0.548 AC: 751889 AN: 1371940 Hom.: 209711 Cov.: 37 AF XY: 0.544 AC XY: 368256 AN XY: 676414

African (AFR) AF: 0.906 AC: 28208 AN: 31148

American (AMR) AF: 0.418 AC: 14131 AN: 33818

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 13367 AN: 24250

East Asian (EAS) AF: 0.662 AC: 23543 AN: 35554

South Asian (SAS) AF: 0.473 AC: 36321 AN: 76718

European-Finnish (FIN) AF: 0.493 AC: 16995 AN: 34480

Middle Eastern (MID) AF: 0.589 AC: 3311 AN: 5622

European-Non Finnish (NFE) AF: 0.544 AC: 583309 AN: 1072984

Other (OTH) AF: 0.570 AC: 32704 AN: 57366

GnomAD4 genome AF: 0.634 AC: 96391 AN: 152090 Hom.: 32696 Cov.: 32 AF XY: 0.628 AC XY: 46688 AN XY: 74332

African (AFR) AF: 0.891 AC: 36984 AN: 41518

American (AMR) AF: 0.489 AC: 7469 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1946 AN: 3470

East Asian (EAS) AF: 0.695 AC: 3590 AN: 5166

South Asian (SAS) AF: 0.476 AC: 2291 AN: 4808

European-Finnish (FIN) AF: 0.488 AC: 5151 AN: 10552

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.543 AC: 36940 AN: 67972

Other (OTH) AF: 0.608 AC: 1284 AN: 2112

Alfa AF: 0.509 Hom.: 2786

Bravo AF: 0.648

Asia WGS AF: 0.655 AC: 2280 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome (1)
-	-	1	Arthrogryposis, distal, with impaired proprioception and touch (1)
-	-	1	Gordon syndrome (1)
-	-	1	Marden-Walker syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.57
PhyloP100		-1.3
PromoterAI		-0.013	Neutral
Mutation Taster		=97/3	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: rs8096037; hg19: chr18-10748603; COSMIC: COSV108125170; COSMIC: COSV108125170;