4-109669323-G-T

Position:

• chr4-109669323-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017918.5(MCUB):​c.451+4929G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.763 in 152,102 control chromosomes in the GnomAD database, including 45,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: 𝑓 0.76 (45287 hom., cov: 32)
• Consequence: MCUB NM_017918.5 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -2.62

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]

MCUB (HGNC:):

CASP6 (HGNC:1507): (caspase 6) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family of enzymes. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic acid residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein is processed by caspases 7, 8 and 10, and is thought to function as a downstream enzyme in the caspase activation cascade. Alternative splicing of this gene results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCUB	NM_017918.5	c.451+4929G>T		intron_variant		ENST00000394650.7	NP_060388.2
CASP6	XM_047416245.1	c.*3342C>A		3_prime_UTR_variant	6/6		XP_047272201.1
MCUB	XM_006714246.4	c.364+4929G>T		intron_variant			XP_006714309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCUB	ENST00000394650.7	c.451+4929G>T		intron_variant		1	NM_017918.5	ENSP00000378145.4
MCUB	ENST00000472310.5	n.580+4929G>T		intron_variant		1
MCUB	ENST00000452915.3	n.546+4929G>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.763 AC: 115944 AN: 151984 Hom.: 45235 Cov.: 32

Gnomad AFR AF: 0.937

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.801

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.689

Gnomad OTH AF: 0.734

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.763 AC: 116048 AN: 152102 Hom.: 45287 Cov.: 32 AF XY: 0.761 AC XY: 56579 AN XY: 74350

Gnomad4 AFR AF: 0.937

Gnomad4 AMR AF: 0.682

Gnomad4 ASJ AF: 0.703

Gnomad4 EAS AF: 0.801

Gnomad4 SAS AF: 0.662

Gnomad4 FIN AF: 0.742

Gnomad4 NFE AF: 0.689

Gnomad4 OTH AF: 0.733

Alfa AF: 0.690 Hom.: 51819

Bravo AF: 0.767

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

not provided

Department of Ophthalmology and Visual Sciences Kyoto University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.47
DANN	Benign	0.099

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: rs4698775; hg19: chr4-110590479;