16-88715641-C-T

Variant names:

• chr16-88715641-C-T
• rs115423293
• NM_001142864.4:c.7530G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001142864.4(PIEZO1):​c.7530G>A​(p.Pro2510Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,550,234 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (19 hom.)
• Consequence: PIEZO1 NM_001142864.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.68
• Publications: 1 publications found

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]

CTU2 (HGNC:28005): (cytosolic thiouridylase subunit 2) This gene encodes a protein which is involved in the post-transcriptional modification of transfer RNAs (tRNAs). The encoded protein plays a role in thiolation of uridine residue present at the wobble position in a subset of tRNAs, resulting in enhanced codon reading accuracy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

CTU2 Gene-Disease associations (from GenCC):

• microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023759902).
• BP6: Variant 16-88715641-C-T is Benign according to our data. Variant chr16-88715641-C-T is described in ClinVar as Benign. ClinVar VariationId is 789647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00745 (1135/152328) while in subpopulation AFR AF = 0.0251 (1042/41574). AF 95% confidence interval is 0.0238. There are 11 homozygotes in GnomAd4. There are 562 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142864.4. 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
	PIEZO1	NM_001142864.4	MANE Select	c.7530G>A	p.Pro2510Pro	synonymous	Exon 51 of 51	NP_001136336.2	Q92508
	CTU2	NM_001012759.3	MANE Select	c.*390C>T		downstream_gene	N/A	NP_001012777.1	Q2VPK5-1
	CTU2	NM_001318507.2		c.*390C>T		downstream_gene	N/A	NP_001305436.1	H3BSW6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.7530G>A	p.Pro2510Pro	synonymous	Exon 51 of 51	ENSP00000301015.9	Q92508
	PIEZO1	ENST00000419505.5	TSL:1	n.*1070G>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000406358.1	H7C2J5
	PIEZO1	ENST00000419505.5	TSL:1	n.*1070G>A		3_prime_UTR	Exon 10 of 10	ENSP00000406358.1	H7C2J5

Frequencies

GnomAD3 genomes AF: 0.00744 AC: 1132 AN: 152210 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00175 AC: 270 AN: 154470 AF XY: 0.00134

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.000917

GnomAD4 exome AF: 0.000874 AC: 1222 AN: 1397906 Hom.: 19 Cov.: 32 AF XY: 0.000719 AC XY: 496 AN XY: 689454

African (AFR) AF: 0.0293 AC: 926 AN: 31596

American (AMR) AF: 0.00162 AC: 58 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25180

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35732

South Asian (SAS) AF: 0.000139 AC: 11 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47882

Middle Eastern (MID) AF: 0.000878 AC: 5 AN: 5698

European-Non Finnish (NFE) AF: 0.0000871 AC: 94 AN: 1078904

Other (OTH) AF: 0.00217 AC: 126 AN: 57978

GnomAD4 genome AF: 0.00745 AC: 1135 AN: 152328 Hom.: 11 Cov.: 33 AF XY: 0.00754 AC XY: 562 AN XY: 74490

African (AFR) AF: 0.0251 AC: 1042 AN: 41574

American (AMR) AF: 0.00438 AC: 67 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68028

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00519 Hom.: 4

Bravo AF: 0.00918

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0275 AC: 38

ESP6500EA AF: 0.000315 AC: 1

ExAC AF: 0.00296 AC: 76

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.079
DANN	Benign	0.90
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.98	T
PhyloP100		-4.7
PROVEAN	Benign	2.3	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.16		Loss of relative solvent accessibility (P = 0.0404)
MVP		0.043
ClinPred		0.012	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs115423293; hg19: chr16-88782049;