6-36959355-C-T

Position:

• chr6-36959355-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_153370.3(PI16):​c.382C>T​(p.His128Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PI16 NM_153370.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

Genes affected

PI16 (HGNC:21245): (peptidase inhibitor 16) Predicted to enable peptidase inhibitor activity. Predicted to be involved in negative regulation of peptidase activity. Predicted to act upstream of or within negative regulation of cell growth involved in cardiac muscle cell development. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PI16	NM_153370.3	c.382C>T	p.His128Tyr	missense_variant	2/7	ENST00000373674.4	NP_699201.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PI16	ENST00000373674.4	c.382C>T	p.His128Tyr	missense_variant	2/7	1	NM_153370.3	ENSP00000362778.3
PI16	ENST00000611814.4	c.382C>T	p.His128Tyr	missense_variant	3/8	5		ENSP00000478888.1
PI16	ENST00000647861.1	c.382C>T	p.His128Tyr	missense_variant	4/9			ENSP00000497550.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.382C>T (p.H128Y) alteration is located in exon 2 (coding exon 2) of the PI16 gene. This alteration results from a C to T substitution at nucleotide position 382, causing the histidine (H) at amino acid position 128 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	.;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	4.0	H;H;H
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.3	.;.;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	.;.;D
Sift4G	Pathogenic	0.0010	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.92, 0.92
MutPred		0.85		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.41
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-36927131;