chr4-103082094-A-G

Position:

• chr4-103082094-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020139.4(BDH2):​c.671T>C​(p.Leu224Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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: BDH2 NM_020139.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

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:):

SLC9B2 (HGNC:25143): (solute carrier family 9 member B2) Sodium hydrogen antiporters, such as NHEDC2, convert the proton motive force established by the respiratory chain or the F1F0 mitochondrial ATPase into sodium gradients that drive other energy-requiring processes, transduce environmental signals into cell responses, or function in drug efflux (Xiang et al., 2007 [PubMed 18000046]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BDH2	NM_020139.4	c.671T>C	p.Leu224Ser	missense_variant	9/10	ENST00000296424.9	NP_064524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BDH2	ENST00000296424.9	c.671T>C	p.Leu224Ser	missense_variant	9/10	1	NM_020139.4	ENSP00000296424.4

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

Jun 11, 2024

The c.671T>C (p.L224S) alteration is located in exon 9 (coding exon 8) of the BDH2 gene. This alteration results from a T to C substitution at nucleotide position 671, causing the leucine (L) at amino acid position 224 to be replaced by a serine (S). 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	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.89		Gain of disorder (P = 0.009);
MVP		0.83
MPC		0.94
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.98

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: chr4-104003251;