rs142542453

chr16-31111999-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_005881.4(BCKDK):c.1066A>T(p.Ser356Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000415 in 1,614,034 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S356S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (2 hom.)
• Consequence: BCKDK NM_005881.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 6.57

Genes affected

BCKDK (HGNC:16902): (branched chain keto acid dehydrogenase kinase) The branched-chain alpha-ketoacid dehydrogenase complex (BCKD) is an important regulator of the valine, leucine, and isoleucine catabolic pathways. The protein encoded by this gene is found in the mitochondrion, where it phosphorylates and inactivates BCKD. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a domain Histidine kinase (size 245) in uniprot entity BCKD_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_005881.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011356086).
• BP6: Variant 16-31111999-A-T is Benign according to our data. Variant chr16-31111999-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289834.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000342 (52/152214) while in subpopulation NFE AF= 0.000338 (23/67990). AF 95% confidence interval is 0.00023. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDK	NM_005881.4	c.1066A>T	p.Ser356Cys	missense_variant	11/12	ENST00000219794.11
BCKDK	NM_001122957.4	c.1066A>T	p.Ser356Cys	missense_variant	11/11
BCKDK	NM_001271926.3	c.976A>T	p.Ser326Cys	missense_variant	10/10
BCKDK	XM_017022859.2	c.1066A>T	p.Ser356Cys	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDK	ENST00000219794.11	c.1066A>T	p.Ser356Cys	missense_variant	11/12	1	NM_005881.4	P1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152096 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000721 AC: 181 AN: 251170 Hom.: 0 AF XY: 0.000685 AC XY: 93 AN XY: 135792

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00904

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000546

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000423 AC: 618 AN: 1461820 Hom.: 2 Cov.: 31 AF XY: 0.000428 AC XY: 311 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00853

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000271

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74416

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.000468

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2016	- -

Seizure Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

New York Genome Center

Feb 07, 2020

- -

Branched-chain keto acid dehydrogenase kinase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Uncertain	2.0	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		0.92	P;.;.;P
Vest4		0.56
MVP		0.90
MPC		1.2
ClinPred		0.053	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.69

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: rs142542453; hg19: chr16-31123320;