rs7821248

Positions:

• chr8-85333547-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000523022.6(CA1):​c.428C>T​(p.Ala143Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,611,646 control chromosomes in the GnomAD database, including 340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.027 (184 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (156 hom.)
• Consequence: CA1 ENST00000523022.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.38

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006014228).
• BP6: Variant 8-85333547-G-A is Benign according to our data. Variant chr8-85333547-G-A is described in ClinVar as [Benign]. Clinvar id is 776361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA1	NM_001128831.4	c.428C>T	p.Ala143Val	missense_variant	5/8	ENST00000523022.6	NP_001122303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA1	ENST00000523022.6	c.428C>T	p.Ala143Val	missense_variant	5/8	1	NM_001128831.4	ENSP00000429798	P1

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 4066 AN: 152138 Hom.: 181 Cov.: 32

Gnomad AFR AF: 0.0925

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.00683 AC: 1713 AN: 250640 Hom.: 56 AF XY: 0.00490 AC XY: 664 AN XY: 135454

Gnomad AFR exome AF: 0.0919

Gnomad AMR exome AF: 0.00475

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00283 AC: 4136 AN: 1459388 Hom.: 156 Cov.: 29 AF XY: 0.00250 AC XY: 1815 AN XY: 726126

Gnomad4 AFR exome AF: 0.0961

Gnomad4 AMR exome AF: 0.00550

Gnomad4 ASJ exome AF: 0.000537

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.00693

GnomAD4 genome AF: 0.0268 AC: 4086 AN: 152258 Hom.: 184 Cov.: 32 AF XY: 0.0254 AC XY: 1891 AN XY: 74454

Gnomad4 AFR AF: 0.0928

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0250

Alfa AF: 0.0104 Hom.: 38

Bravo AF: 0.0300

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0865 AC: 381

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00850 AC: 1032

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T;T;T;T;T;.;T;.;T;T;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	.;.;.;.;D;D;D;D;D;D;D;.;D;D
MetaRNN	Benign	0.0060	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	.;M;M;M;M;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.7	.;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.013	.;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.011	D;T;T;T;T;D;.;D;.;.;.;.;T;.
Polyphen		0.96	.;D;D;D;D;.;.;.;.;.;.;.;.;.
Vest4		0.32
MVP		0.83
MPC		0.040
ClinPred		0.071	T
GERP RS		2.2
Varity_R		0.56
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7821248; hg19: chr8-86245776;