chr12-56774044-G-C

Position:

• chr12-56774044-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003725.4(HSD17B6):​c.192G>C​(p.Lys64Asn) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSD17B6 NM_003725.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0100

Genes affected

HSD17B6 (HGNC:23316): (hydroxysteroid 17-beta dehydrogenase 6) The protein encoded by this gene has both oxidoreductase and epimerase activities and is involved in androgen catabolism. The oxidoreductase activity can convert 3 alpha-adiol to dihydrotestosterone, while the epimerase activity can convert androsterone to epi-androsterone. Both reactions use NAD+ as the preferred cofactor. This gene is a member of the retinol dehydrogenase family. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17582732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B6	NM_003725.4	c.192G>C	p.Lys64Asn	missense_variant	2/5	ENST00000322165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B6	ENST00000322165.1	c.192G>C	p.Lys64Asn	missense_variant	2/5	1	NM_003725.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Mar 22, 2023

The c.192G>C (p.K64N) alteration is located in exon 2 (coding exon 1) of the HSD17B6 gene. This alteration results from a G to C substitution at nucleotide position 192, causing the lysine (K) at amino acid position 64 to be replaced by an asparagine (N). 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	0.21
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.65	D;D;D;T;D;T;D
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	.;.;.;T;.;T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.12	N;N;N;.;N;.;N
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D
REVEL	Benign	0.23
Sift	Benign	0.036	D;D;D;D;D;D;D
Sift4G	Uncertain	0.034	D;D;D;D;D;D;D
Polyphen		0.37	B;B;B;.;B;.;B
Vest4		0.23
MutPred		0.34		Loss of ubiquitination at K64 (P = 0.0155);Loss of ubiquitination at K64 (P = 0.0155);Loss of ubiquitination at K64 (P = 0.0155);Loss of ubiquitination at K64 (P = 0.0155);Loss of ubiquitination at K64 (P = 0.0155);Loss of ubiquitination at K64 (P = 0.0155);Loss of ubiquitination at K64 (P = 0.0155);
MVP		0.63
MPC		0.44
ClinPred		0.28	T
GERP RS		1.3
Varity_R		0.16
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-57167828;