rs4796901

Variant names:

• chr18-10704621-C-G
• rs4796901
• NM_001378183.1:c.6031G>C

Your query was ambiguous. Multiple possible variants found:

• chr18-10704621-C-G
• chr18-10704621-C-T

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.6031G>C​(p.Glu2011Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,536,928 control chromosomes in the GnomAD database, including 42,169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3239 hom., cov: 33)
  • Exomes 𝑓: 0.24 (38930 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.53
• Publications: 15 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: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000264843 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.001565665).
• BP6: Variant 18-10704621-C-G is Benign according to our data. Variant chr18-10704621-C-G is described in ClinVar as Benign. ClinVar VariationId is 261519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.264 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.6031G>C	p.Glu2011Gln	missense	Exon 42 of 56	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.5767G>C	p.Glu1923Gln	missense	Exon 40 of 54	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.5692G>C	p.Glu1898Gln	missense	Exon 38 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.6031G>C	p.Glu2011Gln	missense	Exon 42 of 56	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.5692G>C	p.Glu1898Gln	missense	Exon 38 of 52	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.5767G>C	p.Glu1923Gln	missense	Exon 40 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30696 AN: 152072 Hom.: 3237 Cov.: 33

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.225 AC: 31886 AN: 141604 AF XY: 0.230

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.230

GnomAD4 exome AF: 0.235 AC: 325556 AN: 1384738 Hom.: 38930 Cov.: 33 AF XY: 0.236 AC XY: 161530 AN XY: 683290

African (AFR) AF: 0.146 AC: 4597 AN: 31590

American (AMR) AF: 0.200 AC: 7137 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6142 AN: 25180

East Asian (EAS) AF: 0.180 AC: 6424 AN: 35732

South Asian (SAS) AF: 0.279 AC: 22072 AN: 79230

European-Finnish (FIN) AF: 0.233 AC: 8166 AN: 35000

Middle Eastern (MID) AF: 0.224 AC: 1274 AN: 5692

European-Non Finnish (NFE) AF: 0.238 AC: 256691 AN: 1078708

Other (OTH) AF: 0.225 AC: 13053 AN: 57906

GnomAD4 genome AF: 0.202 AC: 30703 AN: 152190 Hom.: 3239 Cov.: 33 AF XY: 0.202 AC XY: 15045 AN XY: 74406

African (AFR) AF: 0.144 AC: 5975 AN: 41540

American (AMR) AF: 0.189 AC: 2891 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 861 AN: 3470

East Asian (EAS) AF: 0.180 AC: 932 AN: 5182

South Asian (SAS) AF: 0.276 AC: 1328 AN: 4814

European-Finnish (FIN) AF: 0.249 AC: 2640 AN: 10592

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15525 AN: 67984

Other (OTH) AF: 0.202 AC: 427 AN: 2112

Alfa AF: 0.209 Hom.: 2123

Bravo AF: 0.198

TwinsUK AF: 0.242 AC: 897

ALSPAC AF: 0.241 AC: 929

ESP6500AA AF: 0.149 AC: 206

ESP6500EA AF: 0.227 AC: 723

ExAC AF: 0.219 AC: 4437

Asia WGS AF: 0.214 AC: 743 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.32
Sift	Benign	0.063	T
Sift4G	Uncertain	0.0060	D
Vest4		0.24
MPC		0.92
ClinPred		0.020	T
GERP RS		5.4
Varity_R		0.21
gMVP		0.67
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: rs4796901; hg19: chr18-10704619; COSMIC: COSV107250568; COSMIC: COSV107250568;