Variant 8-85338398-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001128831.4(CA1):c.89C>G(p.Ser30Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CA1
NM_001128831.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.24

Variant links:

Genes affected

CA1 (HGNC:1368): (carbonic anhydrase 1) Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. This CA1 gene is closely linked to the CA2 and CA3 genes on chromosome 8. It encodes a cytosolic protein that is found at the highest level in erythrocytes. Allelic variants of this gene have been described in some populations. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Nov 2016]

CA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA1	NM_001128831.4 linkuse as main transcript	c.89C>G	p.Ser30Cys	missense_variant	3/8	ENST00000523022.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA1	ENST00000523022.6 linkuse as main transcript	c.89C>G	p.Ser30Cys	missense_variant	3/8	1	NM_001128831.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.89C>G (p.S30C) alteration is located in exon 4 (coding exon 2) of the CA1 gene. This alteration results from a C to G substitution at nucleotide position 89, causing the serine (S) at amino acid position 30 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.58

D;D;D;D;.;T;T;T;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;.;.;D;D;D;.;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

5.6

H;H;H;H;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-4.8

D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;.;.;D;.;D;D

Polyphen

1.0

D;D;D;D;.;.;.;.;.;.;.

Vest4

0.93

MutPred

0.91

Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);Loss of disorder (P = 0.0057);

MVP

0.97

MPC

0.23

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.94

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over