rs104894559

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5BS1_SupportingBS2

The NM_000717.5(CA4):c.40C>T(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,599,366 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CA4
NM_000717.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: -0.734

Publications

22 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP5

Variant 17-60150074-C-T is Pathogenic according to our data. Variant chr17-60150074-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 17607.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000138 (21/152366) while in subpopulation NFE AF = 0.000176 (12/68038). AF 95% confidence interval is 0.000102. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 21 AD gene.

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.40C>T	p.Arg14Trp	missense	Exon 1 of 8	NP_000708.1	P22748-1
	CA4	NR_137422.2		n.102C>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.40C>T	p.Arg14Trp	missense	Exon 1 of 8	ENSP00000300900.3	P22748-1
CA4	ENST00000904866.1		c.40C>T	p.Arg14Trp	missense	Exon 1 of 9	ENSP00000574925.1
CA4	ENST00000904870.1		c.40C>T	p.Arg14Trp	missense	Exon 1 of 8	ENSP00000574929.1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000248

AC:

AN:

221764

AF XY:

0.000242

show subpopulations

Gnomad AFR exome

AF:

0.000151

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000876

Gnomad NFE exome

AF:

0.000392

Gnomad OTH exome

AF:

0.000536

GnomAD4 exome

AF:

0.000170

AC:

246

AN:

1447000

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

115

AN XY:

720318

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33330

American (AMR)

AF:

0.0000224

AC:

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86050

European-Finnish (FIN)

AF:

0.000612

AC:

AN:

40824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5532

European-Non Finnish (NFE)

AF:

0.000177

AC:

197

AN:

1110916

Other (OTH)

AF:

0.000300

AC:

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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

AF:

0.000138

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41596

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000784

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

CA4-related disorder (1)

not provided (1)

Retinitis pigmentosa (1)

Retinitis pigmentosa 17 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.52

MutationAssessor

Benign

2.0

PhyloP100

-0.73

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.36

Sift

Benign

0.030

Sift4G

Uncertain

0.028

Polyphen

0.99

Vest4

0.22

MVP

0.75

MPC

2.5

ClinPred

0.065

GERP RS

-0.83

PromoterAI

-0.051

Neutral

(source)

Varity_R

0.064

gMVP

0.55

Mutation Taster

=30/70

disease causing (ClinVar)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over