chr4-103095212-T-C

Position:

• chr4-103095212-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020139.4(BDH2):​c.142A>G​(p.Lys48Glu) 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: BDH2 NM_020139.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.163

Genes affected

BDH2 (HGNC:32389): (3-hydroxybutyrate dehydrogenase 2) Enables 3-hydroxybutyrate dehydrogenase activity and NAD binding activity. Involved in epithelial cell differentiation and fatty acid beta-oxidation. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

BDH2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046541244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BDH2	NM_020139.4	c.142A>G	p.Lys48Glu	missense_variant	3/10	ENST00000296424.9	NP_064524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BDH2	ENST00000296424.9	c.142A>G	p.Lys48Glu	missense_variant	3/10	1	NM_020139.4	ENSP00000296424.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Nov 13, 2023

The c.142A>G (p.K48E) alteration is located in exon 3 (coding exon 2) of the BDH2 gene. This alteration results from a A to G substitution at nucleotide position 142, causing the lysine (K) at amino acid position 48 to be replaced by a glutamic acid (E). 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	0.10
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	9.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.18	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.82	T;T;T
Sift4G	Benign	0.99	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.23
MutPred		0.32		Loss of ubiquitination at K48 (P = 0.0148);Loss of ubiquitination at K48 (P = 0.0148);Loss of ubiquitination at K48 (P = 0.0148);
MVP		0.48
MPC		0.29
ClinPred		0.097	T
GERP RS		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.45

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: rs1748336029; hg19: chr4-104016369;