chr16-88715693-A-AGCTCCC

Variant names:

• chr16-88715693-A-AGCTCCC
• rs755226463
• NM_001142864.4:c.7472_7477dupGGGAGC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3 BP3 BS1_Supporting BS2

The NM_001142864.4(PIEZO1):​c.7472_7477dupGGGAGC​(p.Arg2491_Glu2492dup) variant causes a conservative inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000677 in 1,550,262 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: PIEZO1 NM_001142864.4 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 7.96

Genes affected

PIEZO1 (HGNC:28993): (piezo type mechanosensitive ion channel component 1 (Er blood group)) The protein encoded by this gene is a mechanically-activated ion channel that links mechanical forces to biological signals. The encoded protein contains 36 transmembrane domains and functions as a homotetramer. Defects in this gene have been associated with dehydrated hereditary stomatocytosis. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP3: Nonframeshift variant in repetitive region in NM_001142864.4
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000565 (86/152226) while in subpopulation NFE AF= 0.000896 (61/68044). AF 95% confidence interval is 0.000716. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 86 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4	c.7472_7477dupGGGAGC	p.Arg2491_Glu2492dup	conservative_inframe_insertion	Exon 51 of 51	ENST00000301015.14	NP_001136336.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14	c.7472_7477dupGGGAGC	p.Arg2491_Glu2492dup	conservative_inframe_insertion	Exon 51 of 51	1	NM_001142864.4	ENSP00000301015.9

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000896

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000641 AC: 100 AN: 156038 Hom.: 0 AF XY: 0.000616 AC XY: 51 AN XY: 82834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000918

Gnomad SAS exome AF: 0.000351

Gnomad FIN exome AF: 0.00214

Gnomad NFE exome AF: 0.000782

Gnomad OTH exome AF: 0.000455

GnomAD4 exome AF: 0.000690 AC: 964 AN: 1398036 Hom.: 1 Cov.: 35 AF XY: 0.000677 AC XY: 467 AN XY: 689502

Gnomad4 AFR exome AF: 0.000222

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00156

Gnomad4 NFE exome AF: 0.000759

Gnomad4 OTH exome AF: 0.000552

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000538 AC XY: 40 AN XY: 74374

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.000896

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000632 Hom.: 0

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 09, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2022	In-frame insertion of 2 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -

Lymphatic malformation 6;C4551512:Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs755226463; hg19: chr16-88782101;