8-85329771-G-A

Position:

• chr8-85329771-G-A

Variant summary

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

The NM_001128831.4(CA1):​c.587C>T​(p.Pro196Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,605,782 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (61 hom.)
• Consequence: CA1 NM_001128831.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.99

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=0.007695049).
• BP6: Variant 8-85329771-G-A is Benign according to our data. Variant chr8-85329771-G-A is described in ClinVar as [Benign]. Clinvar id is 784132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA1	NM_001128831.4	c.587C>T	p.Pro196Leu	missense_variant	7/8	ENST00000523022.6	NP_001122303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA1	ENST00000523022.6	c.587C>T	p.Pro196Leu	missense_variant	7/8	1	NM_001128831.4	ENSP00000429798.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2193 AN: 152152 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00359 AC: 855 AN: 238220 Hom.: 17 AF XY: 0.00262 AC XY: 336 AN XY: 128302

Gnomad AFR exome AF: 0.0484

Gnomad AMR exome AF: 0.00316

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00162 AC: 2358 AN: 1453514 Hom.: 61 Cov.: 30 AF XY: 0.00139 AC XY: 1005 AN XY: 722230

Gnomad4 AFR exome AF: 0.0552

Gnomad4 AMR exome AF: 0.00332

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000259

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000777

Gnomad4 OTH exome AF: 0.00408

GnomAD4 genome AF: 0.0145 AC: 2207 AN: 152268 Hom.: 52 Cov.: 32 AF XY: 0.0140 AC XY: 1043 AN XY: 74440

Gnomad4 AFR AF: 0.0498

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00307 Hom.: 15

Bravo AF: 0.0163

ESP6500AA AF: 0.0524 AC: 231

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00426 AC: 516

Asia WGS AF: 0.00462 AC: 16 AN: 3478

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	1.1
DANN	Benign	0.57
DEOGEN2	Benign	0.068	T;T;T;T;T;T;T;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.60	.;.;.;.;T;T;T;T;T;D
MetaRNN	Benign	0.0077	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.59	.;N;N;N;N;.;.;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.8	.;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.19
Sift	Benign	0.13	.;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T;.;T;.;.
Polyphen		0.017	.;B;B;B;B;.;.;.;.;.
Vest4		0.23
MVP		0.47
MPC		0.029
ClinPred		0.013	T
GERP RS		-9.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.28

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: rs61734484; hg19: chr8-86242000;