chr4-109659025-G-C

Position:

• chr4-109659025-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017918.5(MCUB):​c.114G>C​(p.Lys38Asn) 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. 13/21 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: MCUB NM_017918.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.316

Genes affected

MCUB (HGNC:26076): (mitochondrial calcium uniporter dominant negative subunit beta) Predicted to enable calcium channel inhibitor activity. Predicted to be involved in calcium import into the mitochondrion and mitochondrial calcium ion homeostasis. Located in mitochondrion and nucleoplasm. Is integral component of mitochondrial inner membrane. Part of uniplex complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13894913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCUB	NM_017918.5	c.114G>C	p.Lys38Asn	missense_variant	2/8	ENST00000394650.7
MCUB	XM_006714246.4	c.27G>C	p.Lys9Asn	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCUB	ENST00000394650.7	c.114G>C	p.Lys38Asn	missense_variant	2/8	1	NM_017918.5	P1
MCUB	ENST00000472310.5	n.243G>C		non_coding_transcript_exon_variant	2/5	1
MCUB	ENST00000452915.3	n.209G>C		non_coding_transcript_exon_variant	3/6	5
MCUB	ENST00000515114.3	n.240G>C		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 02, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS2,PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.054
Sift	Benign	0.037	D
Sift4G	Benign	0.064	T
Polyphen		0.68	P
Vest4		0.14
MutPred		0.47		Loss of methylation at K38 (P = 0.012);
MVP		0.39
MPC		0.25
ClinPred		0.77	D
GERP RS		0.70
Varity_R		0.10
gMVP		0.48

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: rs1729166878; hg19: chr4-110580181;