chr18-10671669-C-T

Variant names:

• chr18-10671669-C-T
• rs189453524
• NM_001378183.1:c.8456G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP4 BP6 BS1

The NM_001378183.1(PIEZO2):​c.8456G>A​(p.Arg2819Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,613,984 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 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PIEZO2 NM_001378183.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.87
• Publications: 6 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.3097222).
• BP6: Variant 18-10671669-C-T is Benign according to our data. Variant chr18-10671669-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 784545.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000361 (55/152264) while in subpopulation AMR AF = 0.00229 (35/15292). AF 95% confidence interval is 0.00169. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.8456G>A	p.Arg2819Gln	missense	Exon 56 of 56	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.8192G>A	p.Arg2731Gln	missense	Exon 54 of 54	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.8117G>A	p.Arg2706Gln	missense	Exon 52 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.8456G>A	p.Arg2819Gln	missense	Exon 56 of 56	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.8117G>A	p.Arg2706Gln	missense	Exon 52 of 52	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.8192G>A	p.Arg2731Gln	missense	Exon 54 of 54	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000275 AC: 69 AN: 251108 AF XY: 0.000280

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000185 AC: 270 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.000187 AC XY: 136 AN XY: 727162

African (AFR) AF: 0.000149 AC: 5 AN: 33472

American (AMR) AF: 0.00145 AC: 65 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000173 AC: 192 AN: 1111954

Other (OTH) AF: 0.000116 AC: 7 AN: 60386

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74444

African (AFR) AF: 0.0000481 AC: 2 AN: 41546

American (AMR) AF: 0.00229 AC: 35 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000412

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
REVEL	Pathogenic	0.65
Sift4G	Uncertain	0.0020	D
Vest4		0.79
MVP		0.25
MPC		0.94
ClinPred		0.40	T
GERP RS		4.6
Varity_R		0.74
gMVP		0.88
Mutation Taster		=42/58	disease causing

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: rs189453524; hg19: chr18-10671666; COSMIC: COSV99554717; COSMIC: COSV99554717;