chr18-10801447-G-C

Variant names:

• chr18-10801447-G-C
• rs7241307
• NM_001378183.1:c.1201-19C>G

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.1201-19C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0634 in 1,495,352 control chromosomes in the GnomAD database, including 3,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (293 hom., cov: 33)
  • Exomes 𝑓: 0.064 (3026 hom.)
• Consequence: PIEZO2 NM_001378183.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.31
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 18-10801447-G-C is Benign according to our data. Variant chr18-10801447-G-C is described in ClinVar as Benign. ClinVar VariationId is 261496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0646 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.1201-19C>G		intron	N/A	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.1201-19C>G		intron	N/A	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.1201-19C>G		intron	N/A	NP_071351.2	Q9H5I5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO2	ENST00000674853.1	MANE Select	c.1201-19C>G		intron	N/A	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.1201-19C>G		intron	N/A	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.1201-19C>G		intron	N/A	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes AF: 0.0562 AC: 8556 AN: 152160 Hom.: 293 Cov.: 33

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.0525

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.0408

Gnomad FIN AF: 0.0878

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.0598

GnomAD2 exomes AF: 0.0519 AC: 7578 AN: 146006 AF XY: 0.0521

Gnomad AFR exome AF: 0.0494

Gnomad AMR exome AF: 0.0401

Gnomad ASJ exome AF: 0.0484

Gnomad EAS exome AF: 0.00216

Gnomad FIN exome AF: 0.0868

Gnomad NFE exome AF: 0.0647

Gnomad OTH exome AF: 0.0582

GnomAD4 exome AF: 0.0643 AC: 86305 AN: 1343074 Hom.: 3026 Cov.: 30 AF XY: 0.0637 AC XY: 42335 AN XY: 664686

African (AFR) AF: 0.0450 AC: 1375 AN: 30588

American (AMR) AF: 0.0434 AC: 1547 AN: 35622

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 1266 AN: 24958

East Asian (EAS) AF: 0.00113 AC: 40 AN: 35516

South Asian (SAS) AF: 0.0432 AC: 3385 AN: 78322

European-Finnish (FIN) AF: 0.0846 AC: 2978 AN: 35210

Middle Eastern (MID) AF: 0.0286 AC: 161 AN: 5634

European-Non Finnish (NFE) AF: 0.0694 AC: 72230 AN: 1040482

Other (OTH) AF: 0.0586 AC: 3323 AN: 56742

GnomAD4 genome AF: 0.0562 AC: 8560 AN: 152278 Hom.: 293 Cov.: 33 AF XY: 0.0566 AC XY: 4213 AN XY: 74458

African (AFR) AF: 0.0462 AC: 1918 AN: 41558

American (AMR) AF: 0.0434 AC: 663 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 182 AN: 3468

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5186

South Asian (SAS) AF: 0.0404 AC: 195 AN: 4826

European-Finnish (FIN) AF: 0.0878 AC: 932 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0662 AC: 4506 AN: 68016

Other (OTH) AF: 0.0596 AC: 126 AN: 2114

Alfa AF: 0.0577 Hom.: 47

Bravo AF: 0.0532

Asia WGS AF: 0.0230 AC: 81 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.41
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs7241307; hg19: chr18-10801445;