NM_001378183.1:c.7349+7C>T

Variant names:

• chr18-10691218-G-A
• rs3748422
• NM_001378183.1:c.7349+7C>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.7349+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,610,936 control chromosomes in the GnomAD database, including 110,021 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (9846 hom., cov: 31)
  • Exomes 𝑓: 0.37 (100175 hom.)
• Consequence: PIEZO2 NM_001378183.1 splice_region, intron
• Scores: Splicing: ADA: 0.00008783
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.471
• Publications: 12 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=-0.83).
• BP6: Variant 18-10691218-G-A is Benign according to our data. Variant chr18-10691218-G-A is described in ClinVar as Benign. ClinVar VariationId is 261527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.378 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.7349+7C>T		splice_region intron	N/A	NP_001365112.1	A0A2H4UKA7
	PIEZO2	NM_001410871.1		c.7085+7C>T		splice_region intron	N/A	NP_001397800.1	Q9H5I5-4
	PIEZO2	NM_022068.4		c.7010+7C>T		splice_region 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.7349+7C>T		splice_region intron	N/A	ENSP00000501957.1	A0A2H4UKA7
	PIEZO2	ENST00000503781.7	TSL:1	c.7010+7C>T		splice_region intron	N/A	ENSP00000421377.3	Q9H5I5-1
	PIEZO2	ENST00000580640.5	TSL:5	c.7085+7C>T		splice_region intron	N/A	ENSP00000463094.1	Q9H5I5-4

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54617 AN: 151788 Hom.: 9841 Cov.: 31

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.290

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.366

GnomAD2 exomes AF: 0.345 AC: 86175 AN: 249850 AF XY: 0.344

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.285

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.297

Gnomad FIN exome AF: 0.362

Gnomad NFE exome AF: 0.380

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.368 AC: 537299 AN: 1459030 Hom.: 100175 Cov.: 34 AF XY: 0.366 AC XY: 265510 AN XY: 725874

African (AFR) AF: 0.350 AC: 11693 AN: 33426

American (AMR) AF: 0.291 AC: 12930 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 9984 AN: 26086

East Asian (EAS) AF: 0.374 AC: 14807 AN: 39636

South Asian (SAS) AF: 0.281 AC: 24116 AN: 85896

European-Finnish (FIN) AF: 0.359 AC: 19194 AN: 53398

Middle Eastern (MID) AF: 0.318 AC: 1832 AN: 5752

European-Non Finnish (NFE) AF: 0.380 AC: 421386 AN: 1110040

Other (OTH) AF: 0.354 AC: 21357 AN: 60304

GnomAD4 genome AF: 0.360 AC: 54637 AN: 151906 Hom.: 9846 Cov.: 31 AF XY: 0.357 AC XY: 26465 AN XY: 74204

African (AFR) AF: 0.353 AC: 14632 AN: 41406

American (AMR) AF: 0.317 AC: 4846 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1376 AN: 3472

East Asian (EAS) AF: 0.308 AC: 1587 AN: 5154

South Asian (SAS) AF: 0.260 AC: 1250 AN: 4804

European-Finnish (FIN) AF: 0.363 AC: 3820 AN: 10536

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.382 AC: 25975 AN: 67956

Other (OTH) AF: 0.362 AC: 763 AN: 2108

Alfa AF: 0.369 Hom.: 7195

Bravo AF: 0.354

Asia WGS AF: 0.264 AC: 921 AN: 3478

EpiCase AF: 0.380

EpiControl AF: 0.368

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.38
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000088
dbscSNV1_RF	Benign	0.0
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: rs3748422; hg19: chr18-10691216; COSMIC: COSV53289402;