Genetic Variant CA4:p.Arg2Trp (chr17-60150038-C-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_000717.5(CA4):c.4C>T(p.Arg2Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R2R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CA4
NM_000717.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.40

Publications

4 publications found

Variant links:

Genes affected

CA4 (HGNC:1375): (carbonic anhydrase 4) 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 gene encodes a glycosylphosphatidyl-inositol-anchored membrane isozyme expressed on the luminal surfaces of pulmonary (and certain other) capillaries and proximal renal tubules. Its exact function is not known; however, it may have a role in inherited renal abnormalities of bicarbonate transport. [provided by RefSeq, Jul 2008]

CA4 Gene-Disease associations (from GenCC):

retinitis pigmentosa 17
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P

CA4 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=0.13317168).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000717.5. 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
	CA4	NM_000717.5	MANE Select	c.4C>T	p.Arg2Trp	missense	Exon 1 of 8	NP_000708.1	P22748-1
	CA4	NR_137422.2		n.66C>T		non_coding_transcript_exon	Exon 1 of 12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CA4	ENST00000300900.9	TSL:1 MANE Select	c.4C>T	p.Arg2Trp	missense	Exon 1 of 8	ENSP00000300900.3	P22748-1
CA4	ENST00000904866.1		c.4C>T	p.Arg2Trp	missense	Exon 1 of 9	ENSP00000574925.1
CA4	ENST00000904870.1		c.4C>T	p.Arg2Trp	missense	Exon 1 of 8	ENSP00000574929.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000881

AC:

AN:

226970

AF XY:

0.0000159

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000707

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449884

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.00

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110866

Other (OTH)

AF:

0.00

AC:

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Uncertain

0.40

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.9

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.23

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.64

PhyloP100

-2.4

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.0

REVEL

Benign

0.15

Sift

Pathogenic

0.0

Sift4G

Benign

0.12

Polyphen

0.0

Vest4

0.15

MutPred

0.49

Loss of disorder (P = 2e-04)

MVP

0.30

MPC

2.5

ClinPred

0.29

GERP RS

-5.4

PromoterAI

0.064

Neutral

(source)

Varity_R

0.064

gMVP

0.58

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