chr16-31109289-A-T

Variant names:

• chr16-31109289-A-T
• rs775340971
• NM_005881.4:c.66A>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_005881.4(BCKDK):​c.66A>T​(p.Gly22Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000381 in 1,601,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: BCKDK NM_005881.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.144
• Publications: 0 publications found

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]

BCKDK Gene-Disease associations (from GenCC):

• branched-chain keto acid dehydrogenase kinase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-31109289-A-T is Benign according to our data. Variant chr16-31109289-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1620858.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.144 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000033 (5/151610) while in subpopulation SAS AF = 0.000838 (4/4776). AF 95% confidence interval is 0.000286. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005881.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDK	NM_005881.4	MANE Select	c.66A>T	p.Gly22Gly	synonymous	Exon 2 of 12	NP_005872.2	O14874-1
	BCKDK	NM_001122957.4		c.66A>T	p.Gly22Gly	synonymous	Exon 2 of 11	NP_001116429.1	O14874-3
	BCKDK	NM_001271926.3		c.66A>T	p.Gly22Gly	synonymous	Exon 2 of 10	NP_001258855.1	O14874-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDK	ENST00000219794.11	TSL:1 MANE Select	c.66A>T	p.Gly22Gly	synonymous	Exon 2 of 12	ENSP00000219794.6	O14874-1
	BCKDK	ENST00000287507.7	TSL:1	c.66A>T	p.Gly22Gly	synonymous	Exon 2 of 10	ENSP00000287507.3	O14874-2
	BCKDK	ENST00000394951.5	TSL:5	c.66A>T	p.Gly22Gly	synonymous	Exon 3 of 13	ENSP00000378405.1	O14874-1

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151492 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000837

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000112 AC: 26 AN: 231174 AF XY: 0.000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000389

Gnomad OTH exome AF: 0.000705

GnomAD4 exome AF: 0.0000386 AC: 56 AN: 1449784 Hom.: 0 Cov.: 33 AF XY: 0.0000555 AC XY: 40 AN XY: 720176

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.000160 AC: 7 AN: 43724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.000421 AC: 36 AN: 85424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50458

Middle Eastern (MID) AF: 0.000524 AC: 3 AN: 5730

European-Non Finnish (NFE) AF: 0.00000542 AC: 6 AN: 1106194

Other (OTH) AF: 0.0000669 AC: 4 AN: 59802

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151610 Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4 AN XY: 74106

African (AFR) AF: 0.00 AC: 0 AN: 41310

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.000838 AC: 4 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67812

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Branched-chain keto acid dehydrogenase kinase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.1
DANN	Benign	0.62
PhyloP100		0.14
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs775340971; hg19: chr16-31120610;