chr16-88715613-T-C

Variant names:

• chr16-88715613-T-C
• rs570744198
• NM_001142864.4:c.7558A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001142864.4(PIEZO1):​c.7558A>G​(p.Lys2520Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000151 in 1,549,598 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 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 4.76
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024006248).
• BP6: Variant 16-88715613-T-C is Benign according to our data. Variant chr16-88715613-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1330570.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000154 (215/1397552) while in subpopulation MID AF = 0.00668 (38/5692). AF 95% confidence interval is 0.005. There are 0 homozygotes in GnomAdExome4. There are 123 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.7558A>G	p.Lys2520Glu	missense	Exon 51 of 51	NP_001136336.2	Q92508
	CTU2	NM_001012759.3	MANE Select	c.*362T>C		downstream_gene	N/A	NP_001012777.1	Q2VPK5-1
	CTU2	NM_001318507.2		c.*362T>C		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.7558A>G	p.Lys2520Glu	missense	Exon 51 of 51	ENSP00000301015.9	Q92508
	PIEZO1	ENST00000419505.5	TSL:1	n.*1098A>G		non_coding_transcript_exon	Exon 10 of 10	ENSP00000406358.1	H7C2J5
	PIEZO1	ENST00000419505.5	TSL:1	n.*1098A>G		3_prime_UTR	Exon 10 of 10	ENSP00000406358.1	H7C2J5

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151928 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000275 AC: 42 AN: 152644 AF XY: 0.000320

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00178

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000516

Gnomad OTH exome AF: 0.000232

GnomAD4 exome AF: 0.000154 AC: 215 AN: 1397552 Hom.: 0 Cov.: 32 AF XY: 0.000178 AC XY: 123 AN XY: 689260

African (AFR) AF: 0.0000950 AC: 3 AN: 31588

American (AMR) AF: 0.000112 AC: 4 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 59 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.000694 AC: 55 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47668

Middle Eastern (MID) AF: 0.00668 AC: 38 AN: 5692

European-Non Finnish (NFE) AF: 0.0000362 AC: 39 AN: 1078796

Other (OTH) AF: 0.000293 AC: 17 AN: 57968

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152046 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74326

African (AFR) AF: 0.0000723 AC: 3 AN: 41482

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67940

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000144

ExAC AF: 0.000473 AC: 12

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.042
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.23
Sift	Benign	0.085	T
Sift4G	Uncertain	0.023	D
Polyphen		0.21	B
Vest4		0.38
MVP		0.19
ClinPred		0.052	T
GERP RS		3.6
Varity_R		0.18
gMVP		0.73
Mutation Taster		=20/80	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: rs570744198; hg19: chr16-88782021;