Genetic Variant NM_198584.3:c.203A>T (chr8-85250905-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198584.3(CA13):c.203A>T(p.Asn68Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N68S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CA13
NM_198584.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.252

Publications

0 publications found

Variant links:

Genes affected

CA13 (HGNC:14914): (carbonic anhydrase 13) Predicted to enable carbonate dehydratase activity. Predicted to be involved in one-carbon metabolic process. Predicted to be located in intracellular membrane-bounded organelle and myelin sheath. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

CA13 links:

ENSG00000258256 (HGNC:):

ENSG00000258256 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23995623).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198584.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA13	NM_198584.3	MANE Select	c.203A>T	p.Asn68Ile	missense	Exon 2 of 7	NP_940986.1	Q8N1Q1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CA13	ENST00000321764.4	TSL:1 MANE Select	c.203A>T	p.Asn68Ile	missense	Exon 2 of 7	ENSP00000318912.3	Q8N1Q1
CA13	ENST00000517298.5	TSL:5	n.792A>T		non_coding_transcript_exon	Exon 3 of 8
ENSG00000258256	ENST00000551479.2	TSL:5	n.79-845T>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.10

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.069

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.039

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.70

PhyloP100

-0.25

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.15

Sift

Benign

0.10

Sift4G

Uncertain

0.040

Polyphen

0.78

Vest4

0.38

MutPred

0.51

Loss of disorder (P = 0.0134)

MVP

0.61

MPC

0.095

ClinPred

0.32

GERP RS

-4.2

Varity_R

0.58

gMVP

0.41

Mutation Taster

=67/33

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over