rs577065337

Variant names:

• chr18-10704429-G-A
• rs577065337
• NM_001378183.1:c.6223C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-10704429-G-A
• chr18-10704429-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.18
• Publications: 1 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 -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

Sel.	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

Sel.	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: 90 AN: 152162 Hom.: 0 Cov.: 33

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: 33 AN: 141708 AF XY: 0.000171

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.: 0 Cov.: 30 AF XY: 0.000126 AC XY: 86 AN XY: 683394

African (AFR) AF: 0.00193 AC: 61 AN: 31592

American (AMR) AF: 0.000308 AC: 11 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

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

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79234

European-Finnish (FIN) AF: 0.000143 AC: 5 AN: 34998

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5694

European-Non Finnish (NFE) AF: 0.0000779 AC: 84 AN: 1078886

Other (OTH) AF: 0.000311 AC: 18 AN: 57916

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74458

African (AFR) AF: 0.00183 AC: 76 AN: 41564

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000579 Hom.: 0

Bravo AF: 0.000586

ExAC AF: 0.000181 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Arthrogryposis, distal, with impaired proprioception and touch (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	26
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.49
MutPred		0.68		Loss of MoRF binding (P = 0.0635)
MVP		0.043
MPC		1.0
ClinPred		0.16	T
GERP RS		1.8
Varity_R		0.27
gMVP		0.72
Mutation Taster		=58/42	polymorphism

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: rs577065337; hg19: chr18-10704427;