8-85332503-G-A

Position:

• chr8-85332503-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001128831.4(CA1):​c.500C>T​(p.Ala167Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,612,212 control chromosomes in the GnomAD database, including 114 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 0.0071 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (109 hom.)
• Consequence: CA1 NM_001128831.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.38

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=0.007727653).
• BP6: Variant 8-85332503-G-A is Benign according to our data. Variant chr8-85332503-G-A is described in ClinVar as [Benign]. Clinvar id is 786412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00829 (12108/1460026) while in subpopulation MID AF= 0.048 (275/5734). AF 95% confidence interval is 0.0433. There are 109 homozygotes in gnomad4_exome. There are 6379 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA1	NM_001128831.4	c.500C>T	p.Ala167Val	missense_variant	6/8	ENST00000523022.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA1	ENST00000523022.6	c.500C>T	p.Ala167Val	missense_variant	6/8	1	NM_001128831.4	P1

Frequencies

GnomAD3 genomes AF: 0.00706 AC: 1074 AN: 152068 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.00839

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.00613

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00887

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00942 AC: 2364 AN: 250834 Hom.: 24 AF XY: 0.0104 AC XY: 1413 AN XY: 135548

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00677

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.00592

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.00829 AC: 12108 AN: 1460026 Hom.: 109 Cov.: 29 AF XY: 0.00878 AC XY: 6379 AN XY: 726380

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00725

Gnomad4 ASJ exome AF: 0.0352

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.00629

Gnomad4 NFE exome AF: 0.00774

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00705 AC: 1073 AN: 152186 Hom.: 5 Cov.: 32 AF XY: 0.00685 AC XY: 510 AN XY: 74400

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00837

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00913

Gnomad4 FIN AF: 0.00613

Gnomad4 NFE AF: 0.00887

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0106 Hom.: 26

Bravo AF: 0.00732

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00904 AC: 1097

Asia WGS AF: 0.00491 AC: 17 AN: 3474

EpiCase AF: 0.0134

EpiControl AF: 0.0149

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	Jul 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.069	T;T;T;T;T;.;T;.;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.83	.;.;.;T;T;T;T;D;T
MetaRNN	Benign	0.0077	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M;M;M;M;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.041	D;D;D;D;D;D;D;T;D
Sift4G	Benign	0.50	T;T;T;T;.;T;.;.;.
Polyphen		0.45	B;B;B;B;.;.;.;.;.
Vest4		0.18
MVP		0.73
MPC		0.041
ClinPred		0.0087	T
GERP RS		1.4
Varity_R		0.26
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61734485; hg19: chr8-86244732;