rs118203931

Positions:

• chr8-85465289-A-C
• chr8-85465289-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 4P and 14B. PM1 PM5 BP4_Strong BP6_Moderate BS1 BS2

The NM_000067.3(CA2):​c.52A>C​(p.Lys18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,614,032 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K18E) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (6 hom.)
• Consequence: CA2 NM_000067.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.252

Genes affected

CA2 (HGNC:1373): (carbonic anhydrase 2) The protein encoded by this gene is one of several isozymes of carbonic anhydrase, which catalyzes reversible hydration of carbon dioxide. Defects in this enzyme are associated with osteopetrosis and renal tubular acidosis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a chain Carbonic anhydrase 2 (size 258) in uniprot entity CAH2_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_000067.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-85465289-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 914.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0049146116).
• BP6: Variant 8-85465289-A-C is Benign according to our data. Variant chr8-85465289-A-C is described in ClinVar as [Benign]. Clinvar id is 2069442.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000131 (20/152298) while in subpopulation SAS AF= 0.00415 (20/4820). AF 95% confidence interval is 0.00275. There are 1 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA2	NM_000067.3	c.52A>C	p.Lys18Gln	missense_variant	2/7	ENST00000285379.10
CA2	NM_001293675.2	c.-133A>C		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA2	ENST00000285379.10	c.52A>C	p.Lys18Gln	missense_variant	2/7	1	NM_000067.3	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152180 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000461 AC: 116 AN: 251464 Hom.: 3 AF XY: 0.000611 AC XY: 83 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00366

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000254 AC: 371 AN: 1461734 Hom.: 6 Cov.: 31 AF XY: 0.000363 AC XY: 264 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00412

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152298 Hom.: 1 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000882 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Benign	0.054	T
Sift4G	Benign	0.18	T
Polyphen		0.0090	B
Vest4		0.22
MutPred		0.42		Loss of ubiquitination at K18 (P = 0.0081);
MVP		0.81
MPC		0.28
ClinPred		0.016	T
GERP RS		1.6
Varity_R		0.49
gMVP		0.56

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: rs118203931; hg19: chr8-86377518;