chr8-85448118-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005181.4(CA3):ā€‹c.748A>Gā€‹(p.Ile250Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000072 ( 0 hom., cov: 32)
Exomes š‘“: 0.000034 ( 0 hom. )

Consequence

CA3
NM_005181.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.170
Variant links:
Genes affected
CA3 (HGNC:1374): (carbonic anhydrase 3) Carbonic anhydrase III (CAIII) is a member of a multigene family (at least six separate genes are known) that encodes carbonic anhydrase isozymes. These carbonic anhydrases are a class of metalloenzymes that catalyze the reversible hydration of carbon dioxide and are differentially expressed in a number of cell types. The expression of the CA3 gene is strictly tissue specific and present at high levels in skeletal muscle and much lower levels in cardiac and smooth muscle. A proportion of carriers of Duchenne muscle dystrophy have a higher CA3 level than normal. The gene spans 10.3 kb and contains seven exons and six introns. [provided by RefSeq, Oct 2008]
CA3-AS1 (HGNC:51657): (CA3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.010671437).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CA3NM_005181.4 linkuse as main transcriptc.748A>G p.Ile250Val missense_variant 7/7 ENST00000285381.3 NP_005172.1
CA3-AS1NR_121630.1 linkuse as main transcriptn.401-5881T>C intron_variant, non_coding_transcript_variant
CA3-AS1NR_121631.1 linkuse as main transcriptn.173-5881T>C intron_variant, non_coding_transcript_variant
CA3-AS1NR_121632.1 linkuse as main transcriptn.190-5881T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CA3ENST00000285381.3 linkuse as main transcriptc.748A>G p.Ile250Val missense_variant 7/71 NM_005181.4 ENSP00000285381 P1
CA3-AS1ENST00000521761.6 linkuse as main transcriptn.401-5881T>C intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00115
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000719
AC:
18
AN:
250256
Hom.:
0
AF XY:
0.0000666
AC XY:
9
AN XY:
135226
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000118
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000490
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000335
AC:
49
AN:
1461136
Hom.:
0
Cov.:
31
AF XY:
0.0000344
AC XY:
25
AN XY:
726836
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000897
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000277
Gnomad4 SAS exome
AF:
0.0000465
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152300
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000964
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000847
Hom.:
0
ExAC
AF:
0.000107
AC:
13
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.0000546
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 03, 2021The c.748A>G (p.I250V) alteration is located in exon 7 (coding exon 7) of the CA3 gene. This alteration results from a A to G substitution at nucleotide position 748, causing the isoleucine (I) at amino acid position 250 to be replaced by a valine (V). 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
Benign
0.076
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
4.4
DANN
Benign
0.90
DEOGEN2
Benign
0.15
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.061
N
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.011
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.075
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.88
N
REVEL
Benign
0.28
Sift
Uncertain
0.029
D
Sift4G
Uncertain
0.046
D
Polyphen
0.0
B
Vest4
0.040
MVP
0.25
MPC
0.13
ClinPred
0.029
T
GERP RS
-12
Varity_R
0.16
gMVP
0.53

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs190933299; hg19: chr8-86360347; API