Genetic Variant SDR16C5:p.Tyr272Cys (chr8-56305618-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138969.4(SDR16C5):c.815A>G(p.Tyr272Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000486 in 1,439,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

SDR16C5
NM_138969.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.10

Variant links:

Genes affected

SDR16C5 (HGNC:30311): (short chain dehydrogenase/reductase family 16C member 5) This gene encodes a member of the short-chain alcohol dehydrogenase/reductase superfamily of proteins and is involved in the oxidation of retinol to retinaldehyde. The encoded protein is associated with the endoplasmic reticulum and is predicted to contain three transmembrane helices, suggesting that it is an integral membrane protein. It recognizes all-trans-retinol and all-trans-retinaldehyde as substrates and exhibits a strong preference for NAD(+)/NADH as cofactors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

SDR16C5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDR16C5	NM_138969.4 link	c.815A>G	p.Tyr272Cys	missense_variant	Exon 6 of 7	ENST00000303749.8	NP_620419.2	Q8N3Y7-1B3KT84
SDR16C5	NM_001318049.2 link	c.815A>G	p.Tyr272Cys	missense_variant	Exon 6 of 8		NP_001304978.1	Q8N3Y7G3V145B3KT84
SDR16C5	NM_001318050.2 link	c.683A>G	p.Tyr228Cys	missense_variant	Exon 5 of 6		NP_001304979.1	Q8N3Y7-2B3KT84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SDR16C5	ENST00000303749.8 link	c.815A>G	p.Tyr272Cys	missense_variant	Exon 6 of 7	1	NM_138969.4	ENSP00000307607.3	Q8N3Y7-1
SDR16C5	ENST00000396721.6 link	c.683A>G	p.Tyr228Cys	missense_variant	Exon 5 of 6	1		ENSP00000379947.2	Q8N3Y7-2
SDR16C5	ENST00000522671.1 link	c.815A>G	p.Tyr272Cys	missense_variant	Exon 6 of 8	2		ENSP00000431010.1	G3V145

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000130

AC:

AN:

231100

Hom.:

AF XY:

0.00000800

AC XY:

AN XY:

125036

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000276

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000486

AC:

AN:

1439784

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

715406

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000633

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.815A>G (p.Y272C) alteration is located in exon 6 (coding exon 5) of the SDR16C5 gene. This alteration results from a A to G substitution at nucleotide position 815, causing the tyrosine (Y) at amino acid position 272 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

0.20

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.31

.;T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.81

T;T;T

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.46

T;T;T

MetaSVM

Uncertain

0.018

MutationAssessor

Pathogenic

3.6

.;H;.

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-7.0

D;D;D

REVEL

Uncertain

0.53

Sift

Benign

0.039

D;D;D

Sift4G

Benign

0.097

T;T;T

Polyphen

0.042

B;B;B

Vest4

0.50

MutPred

0.50

.;Gain of methylation at K269 (P = 0.0589);Gain of methylation at K269 (P = 0.0589);

MVP

0.83

MPC

0.29

ClinPred

0.96

GERP RS

4.5

Varity_R

0.32

gMVP

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over