rs1763415527

Variant names:

• chr6-36963046-C-G
• rs1763415527
• NM_153370.3:c.704C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-36963046-C-G
• chr6-36963046-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153370.3(PI16):​c.704C>G​(p.Ser235Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PI16 NM_153370.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30210614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PI16	NM_153370.3	c.704C>G	p.Ser235Cys	missense_variant	Exon 5 of 7	ENST00000373674.4	NP_699201.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PI16	ENST00000373674.4	c.704C>G	p.Ser235Cys	missense_variant	Exon 5 of 7	1	NM_153370.3	ENSP00000362778.3
PI16	ENST00000611814.4	c.704C>G	p.Ser235Cys	missense_variant	Exon 6 of 8	5		ENSP00000478888.1
PI16	ENST00000647861.1	c.704C>G	p.Ser235Cys	missense_variant	Exon 7 of 9			ENSP00000497550.1
PI16	ENST00000491324.1	n.44+13C>G		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.704C>G (p.S235C) alteration is located in exon 5 (coding exon 5) of the PI16 gene. This alteration results from a C to G substitution at nucleotide position 704, causing the serine (S) at amino acid position 235 to be replaced by a cysteine (C). 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	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T;T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.34	.;T;.
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	.;.;N
REVEL	Benign	0.18
Sift	Uncertain	0.026	.;.;D
Sift4G	Uncertain	0.043	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.36, 0.36
MutPred		0.30		Loss of disorder (P = 0.0102);Loss of disorder (P = 0.0102);Loss of disorder (P = 0.0102);
MVP		0.46
MPC		0.77
ClinPred		0.83	D
GERP RS		4.6
Varity_R		0.14
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs1763415527; hg19: chr6-36930822;