8-85336947-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001128831.4(CA1):c.352G>A(p.Glu118Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,573,870 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: CA1 NM_001128831.4 missense, splice_region
• Scores: Splicing: ADA: 0.9354
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA1	NM_001128831.4	c.352G>A	p.Glu118Lys	missense_variant, splice_region_variant	4/8	ENST00000523022.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA1	ENST00000523022.6	c.352G>A	p.Glu118Lys	missense_variant, splice_region_variant	4/8	1	NM_001128831.4	P1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 250882 Hom.: 0 AF XY: 0.000266 AC XY: 36 AN XY: 135554

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000193 AC: 275 AN: 1421634 Hom.: 1 Cov.: 25 AF XY: 0.000183 AC XY: 130 AN XY: 709666

Gnomad4 AFR exome AF: 0.0000920

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.000824

Gnomad4 NFE exome AF: 0.000194

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74436

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000273 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.352G>A (p.E118K) alteration is located in exon 5 (coding exon 3) of the CA1 gene. This alteration results from a G to A substitution at nucleotide position 352, causing the glutamic acid (E) at amino acid position 118 to be replaced by a lysine (K). 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	0.96
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D;D;D;T;.;T;T;T;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	5.6	H;H;H;H;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.82
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
Polyphen		1.0	D;D;D;D;.;.;.;.;.;.;.
Vest4		0.94
MVP		0.95
MPC		0.24
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.76
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: rs202131223; hg19: chr8-86249176; COSMIC: COSV56278712; COSMIC: COSV56278712;