rs7407105

Variant names:

• chr18-10758025-G-A
• rs7407105
• NM_001378183.1:c.3867C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-10758025-G-A
• chr18-10758025-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378183.1(PIEZO2):​c.3867C>T​(p.Asn1289Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.799 in 1,536,722 control chromosomes in the GnomAD database, including 491,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (50785 hom., cov: 31)
  • Exomes 𝑓: 0.80 (441099 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.53
• Publications: 16 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 18-10758025-G-A is Benign according to our data. Variant chr18-10758025-G-A is described in ClinVar as Benign. ClinVar VariationId is 261507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.889 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.3867C>T	p.Asn1289Asn	synonymous	Exon 27 of 56	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.3867C>T	p.Asn1289Asn	synonymous	Exon 27 of 54	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.3792C>T	p.Asn1264Asn	synonymous	Exon 25 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.3867C>T	p.Asn1289Asn	synonymous	Exon 27 of 56	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.3792C>T	p.Asn1264Asn	synonymous	Exon 25 of 52	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.3867C>T	p.Asn1289Asn	synonymous	Exon 27 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes AF: 0.815 AC: 123883 AN: 151980 Hom.: 50739 Cov.: 31

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.809

GnomAD2 exomes AF: 0.791 AC: 114815 AN: 145116 AF XY: 0.790

Gnomad AFR exome AF: 0.884

Gnomad AMR exome AF: 0.720

Gnomad ASJ exome AF: 0.839

Gnomad EAS exome AF: 0.910

Gnomad FIN exome AF: 0.775

Gnomad NFE exome AF: 0.795

Gnomad OTH exome AF: 0.803

GnomAD4 exome AF: 0.798 AC: 1104303 AN: 1384624 Hom.: 441099 Cov.: 54 AF XY: 0.796 AC XY: 544012 AN XY: 683240

African (AFR) AF: 0.881 AC: 27817 AN: 31590

American (AMR) AF: 0.725 AC: 25858 AN: 35662

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 21066 AN: 25166

East Asian (EAS) AF: 0.900 AC: 32158 AN: 35728

South Asian (SAS) AF: 0.762 AC: 60373 AN: 79216

European-Finnish (FIN) AF: 0.774 AC: 27148 AN: 35068

Middle Eastern (MID) AF: 0.830 AC: 4723 AN: 5692

European-Non Finnish (NFE) AF: 0.796 AC: 858294 AN: 1078552

Other (OTH) AF: 0.809 AC: 46866 AN: 57950

GnomAD4 genome AF: 0.815 AC: 123989 AN: 152098 Hom.: 50785 Cov.: 31 AF XY: 0.814 AC XY: 60513 AN XY: 74340

African (AFR) AF: 0.883 AC: 36626 AN: 41492

American (AMR) AF: 0.753 AC: 11518 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2928 AN: 3468

East Asian (EAS) AF: 0.911 AC: 4704 AN: 5164

South Asian (SAS) AF: 0.762 AC: 3674 AN: 4820

European-Finnish (FIN) AF: 0.788 AC: 8329 AN: 10572

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.788 AC: 53594 AN: 67980

Other (OTH) AF: 0.812 AC: 1714 AN: 2110

Alfa AF: 0.791 Hom.: 6529

Bravo AF: 0.817

Asia WGS AF: 0.867 AC: 3018 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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	-0.46
CADD	Benign	9.7
DANN	Benign	0.77
PhyloP100		1.5
Mutation Taster		=100/0	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: rs7407105; hg19: chr18-10758023; COSMIC: COSV105118988; COSMIC: COSV105118988;