dbSNP rs1042891: CASP6:c.*400T>C (chr4-109688930-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001226.4(CASP6):c.*400T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 156,256 control chromosomes in the GnomAD database, including 37,276 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 36217 hom., cov: 28)

Exomes 𝑓: 0.62 ( 1059 hom. )

Consequence

CASP6
NM_001226.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.73

Publications

10 publications found

Variant links:

Genes affected

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]

CASP6 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP6	NM_001226.4 link	c.*400T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000265164.7	NP_001217.2	P55212-1
MCUB	NM_017918.5 link	c.*1338A>G		downstream_gene_variant		ENST00000394650.7	NP_060388.2	Q9NWR8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP6	ENST00000265164.7 link	c.*400T>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_001226.4	ENSP00000265164.2		P55212-1
MCUB	ENST00000394650.7 link	c.*1338A>G		downstream_gene_variant		1	NM_017918.5	ENSP00000378145.4		Q9NWR8

Frequencies

GnomAD3 genomes

AF:

0.689

AC:

103901

AN:

150788

Hom.:

36169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.783

Gnomad AMI

AF:

0.687

Gnomad AMR

AF:

0.620

Gnomad ASJ

AF:

0.597

Gnomad EAS

AF:

0.533

Gnomad SAS

AF:

0.738

Gnomad FIN

AF:

0.673

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.664

Gnomad OTH

AF:

0.669

GnomAD4 exome

AF:

0.615

AC:

3298

AN:

5362

Hom.:

1059

Cov.:

AF XY:

0.611

AC XY:

1699

AN XY:

2780

show subpopulations

African (AFR)

AF:

0.662

AC:

AN:

American (AMR)

AF:

0.586

AC:

684

AN:

1168

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

AN:

East Asian (EAS)

AF:

0.463

AC:

173

AN:

374

South Asian (SAS)

AF:

0.668

AC:

393

AN:

588

European-Finnish (FIN)

AF:

0.565

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.642

AC:

1822

AN:

2840

Other (OTH)

AF:

0.616

AC:

117

AN:

190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.689

AC:

104000

AN:

150894

Hom.:

36217

Cov.:

AF XY:

0.686

AC XY:

50519

AN XY:

73602

show subpopulations

African (AFR)

AF:

0.783

AC:

32142

AN:

41040

American (AMR)

AF:

0.620

AC:

9428

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.597

AC:

2070

AN:

3466

East Asian (EAS)

AF:

0.534

AC:

2727

AN:

5108

South Asian (SAS)

AF:

0.739

AC:

3547

AN:

4802

European-Finnish (FIN)

AF:

0.673

AC:

6824

AN:

10136

Middle Eastern (MID)

AF:

0.629

AC:

185

AN:

294

European-Non Finnish (NFE)

AF:

0.664

AC:

45040

AN:

67830

Other (OTH)

AF:

0.673

AC:

1415

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1580

3160

4741

6321

7901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.681

Hom.:

12665

Bravo

AF:

0.687

Asia WGS

AF:

0.702

AC:

2439

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.36

(source)

DANN

Benign

0.45

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs1042891

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over