15-43599215-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001375484.1(CKMT1B):c.1196G>A(p.Arg399His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00688 in 1,613,626 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0059 (17 hom., cov: 30)
  • Exomes 𝑓: 0.0070 (174 hom.)
• Consequence: CKMT1B NM_001375484.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.52

Genes affected

CKMT1B (HGNC:1995): (creatine kinase, mitochondrial 1B) Mitochondrial creatine (MtCK) kinase is responsible for the transfer of high energy phosphate from mitochondria to the cytosolic carrier, creatine. It belongs to the creatine kinase isoenzyme family. It exists as two isoenzymes, sarcomeric MtCK and ubiquitous MtCK, encoded by separate genes. Mitochondrial creatine kinase occurs in two different oligomeric forms: dimers and octamers, in contrast to the exclusively dimeric cytosolic creatine kinase isoenzymes. Many malignant cancers with poor prognosis have shown overexpression of ubiquitous mitochondrial creatine kinase; this may be related to high energy turnover and failure to eliminate cancer cells via apoptosis. Ubiquitous mitochondrial creatine kinase has 80% homology with the coding exons of sarcomeric mitochondrial creatine kinase. Two genes located near each other on chromosome 15 have been identified which encode identical mitochondrial creatine kinase proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012996405).
• BP6: Variant 15-43599215-G-A is Benign according to our data. Variant chr15-43599215-G-A is described in ClinVar as [Benign]. Clinvar id is 778548.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00589 (895/151904) while in subpopulation SAS AF= 0.0219 (105/4802). AF 95% confidence interval is 0.0185. There are 17 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CKMT1B	NM_001375484.1	c.1196G>A	p.Arg399His	missense_variant	9/9	ENST00000441322.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CKMT1B	ENST00000441322.6	c.1196G>A	p.Arg399His	missense_variant	9/9	1	NM_001375484.1	P1
CKMT1B	ENST00000300283.10	c.1196G>A	p.Arg399His	missense_variant	10/10	5		P1
CKMT1B	ENST00000437534.3	c.*1116G>A		3_prime_UTR_variant, NMD_transcript_variant	9/9	2

Frequencies

GnomAD3 genomes AF: 0.00581 AC: 882 AN: 151788 Hom.: 15 Cov.: 30

Gnomad AFR AF: 0.00470

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0223

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00337

GnomAD3 exomes AF: 0.00623 AC: 1567 AN: 251408 Hom.: 31 AF XY: 0.00729 AC XY: 990 AN XY: 135878

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0185

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00665

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00698 AC: 10209 AN: 1461722 Hom.: 174 Cov.: 32 AF XY: 0.00747 AC XY: 5434 AN XY: 727166

Gnomad4 AFR exome AF: 0.00394

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0190

Gnomad4 FIN exome AF: 0.000637

Gnomad4 NFE exome AF: 0.00701

Gnomad4 OTH exome AF: 0.00654

GnomAD4 genome AF: 0.00589 AC: 895 AN: 151904 Hom.: 17 Cov.: 30 AF XY: 0.00599 AC XY: 445 AN XY: 74266

Gnomad4 AFR AF: 0.00505

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0219

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00707

Gnomad4 OTH AF: 0.00333

Alfa AF: 0.00700 Hom.: 3

Bravo AF: 0.00545

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00710 AC: 61

ExAC AF: 0.00672 AC: 816

EpiCase AF: 0.00769

EpiControl AF: 0.00771

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.048	D;D
Vest4		0.46
MVP		0.44
MPC		1.1
ClinPred		0.029	T
GERP RS		4.0
gMVP		0.50

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: rs149544188; hg19: chr15-43891413;