NM_001378183.1:c.6223C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001378183.1(PIEZO2):c.6223C>T(p.Arg2075Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000178 in 1,537,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

PIEZO2
NM_001378183.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.18

Publications

1 publications found

Variant links:

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

PIEZO2 links:

ENSG00000264843 (HGNC:):

ENSG00000264843 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027192831).

BP6

Variant 18-10704429-G-A is Benign according to our data. Variant chr18-10704429-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547940.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000591 (90/152278) while in subpopulation AFR AF = 0.00183 (76/41564). AF 95% confidence interval is 0.0015. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIEZO2	NM_001378183.1	MANE Select	c.6223C>T	p.Arg2075Cys	missense	Exon 42 of 56	NP_001365112.1	A0A2H4UKA7
PIEZO2	NM_001410871.1		c.5959C>T	p.Arg1987Cys	missense	Exon 40 of 54	NP_001397800.1	Q9H5I5-4
PIEZO2	NM_022068.4		c.5884C>T	p.Arg1962Cys	missense	Exon 38 of 52	NP_071351.2	Q9H5I5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIEZO2	ENST00000674853.1	MANE Select	c.6223C>T	p.Arg2075Cys	missense	Exon 42 of 56	ENSP00000501957.1	A0A2H4UKA7
PIEZO2	ENST00000503781.7	TSL:1	c.5884C>T	p.Arg1962Cys	missense	Exon 38 of 52	ENSP00000421377.3	Q9H5I5-1
PIEZO2	ENST00000580640.5	TSL:5	c.5959C>T	p.Arg1987Cys	missense	Exon 40 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000233

AC:

AN:

141708

AF XY:

0.000171

show subpopulations

Gnomad AFR exome

AF:

0.00199

Gnomad AMR exome

AF:

0.000325

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000155

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

183

AN:

1384936

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

683394

show subpopulations

African (AFR)

AF:

0.00193

AC:

AN:

31592

American (AMR)

AF:

0.000308

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.000143

AC:

AN:

34998

Middle Eastern (MID)

AF:

0.000527

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000779

AC:

AN:

1078886

Other (OTH)

AF:

0.000311

AC:

AN:

57916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000591

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

41564

American (AMR)

AF:

0.000327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000579

Hom.:

Bravo

AF:

0.000586

ExAC

AF:

0.000181

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arthrogryposis, distal, with impaired proprioception and touch (2)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.27

Eigen

Benign

0.13

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.032

MetaRNN

Benign

0.027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

4.2

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.2

REVEL

Benign

0.26

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.49

MutPred

0.68

Loss of MoRF binding (P = 0.0635)

MVP

0.043

MPC

1.0

ClinPred

0.16

GERP RS

1.8

Varity_R

0.27

gMVP

0.72

Mutation Taster

=58/42

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over