NM_001378183.1:c.3036A>T

Variant names:

• chr18-10763009-T-A
• rs7227167
• NM_001378183.1:c.3036A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_001378183.1(PIEZO2):​c.3036A>T​(p.Thr1012Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000592 in 1,384,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. T1012T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.382
• Publications: 19 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=-0.382 with no splicing effect.

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.3036A>T	p.Thr1012Thr	synonymous	Exon 22 of 56	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.3036A>T	p.Thr1012Thr	synonymous	Exon 22 of 54	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.2961A>T	p.Thr987Thr	synonymous	Exon 20 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.3036A>T	p.Thr1012Thr	synonymous	Exon 22 of 56	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.2961A>T	p.Thr987Thr	synonymous	Exon 20 of 52	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.3036A>T	p.Thr1012Thr	synonymous	Exon 22 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.0000207 AC: 3 AN: 144596 AF XY: 0.0000259

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000505

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000592 AC: 82 AN: 1384958 Hom.: 0 Cov.: 59 AF XY: 0.0000498 AC XY: 34 AN XY: 683394

African (AFR) AF: 0.0000317 AC: 1 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000732 AC: 79 AN: 1078882

Other (OTH) AF: 0.0000345 AC: 2 AN: 57928

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 15506

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.23
DANN	Benign	0.50
PhyloP100		-0.38

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: rs7227167; hg19: chr18-10763007;