Genetic Variant CABP4:p.Arg18His (chr11-67455476-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_145200.5(CABP4):c.53G>A(p.Arg18His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000928 in 1,610,720 control chromosomes in the GnomAD database, including 8 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0038 ( 5 hom., cov: 33)

Exomes 𝑓: 0.00063 ( 3 hom. )

Consequence

CABP4
NM_145200.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.155

Publications

5 publications found

Variant links:

Genes affected

CABP4 (HGNC:1386): (calcium binding protein 4) This gene encodes a member of the CABP family of calcium binding protein characterized by four EF-hand motifs. Mutations in this gene are associated with congenital stationary night blindness type 2B. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

CABP4 Gene-Disease associations (from GenCC):

cone-rod synaptic disorder, congenital nonprogressive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital stationary night blindness
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CABP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071252286).

BP6

Variant 11-67455476-G-A is Benign according to our data. Variant chr11-67455476-G-A is described in ClinVar as Benign. ClinVar VariationId is 305639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00379 (577/152322) while in subpopulation AFR AF = 0.0124 (514/41578). AF 95% confidence interval is 0.0115. There are 5 homozygotes in GnomAd4. There are 273 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145200.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CABP4	NM_145200.5	MANE Select	c.53G>A	p.Arg18His	missense	Exon 1 of 6	NP_660201.1	P57796-1
CABP4	NM_001300895.3		c.-331G>A		5_prime_UTR	Exon 1 of 6	NP_001287824.1	P57796-2
CABP4	NM_001379183.1		c.-345G>A		5_prime_UTR	Exon 4 of 9	NP_001366112.1	P57796-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CABP4	ENST00000325656.7	TSL:1 MANE Select	c.53G>A	p.Arg18His	missense	Exon 1 of 6	ENSP00000324960.5	P57796-1
CABP4	ENST00000438189.6	TSL:1	c.-112-233G>A		intron	N/A	ENSP00000401555.2	P57796-2
CABP4	ENST00000538060.1	TSL:4	n.338G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

573

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00153

AC:

365

AN:

239230

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.00100

Gnomad ASJ exome

AF:

0.00729

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000103

Gnomad OTH exome

AF:

0.00120

GnomAD4 exome

AF:

0.000629

AC:

918

AN:

1458398

Hom.:

Cov.:

AF XY:

0.000655

AC XY:

475

AN XY:

725268

show subpopulations

African (AFR)

AF:

0.0113

AC:

377

AN:

33466

American (AMR)

AF:

0.00108

AC:

AN:

44344

Ashkenazi Jewish (ASJ)

AF:

0.00755

AC:

196

AN:

25946

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00188

AC:

161

AN:

85708

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52086

Middle Eastern (MID)

AF:

0.000529

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

1111240

Other (OTH)

AF:

0.00116

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00379

AC:

577

AN:

152322

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

273

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0124

AC:

514

AN:

41578

American (AMR)

AF:

0.000719

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00311

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68020

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

143

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:

0.00118

Hom.:

Bravo

AF:

0.00416

ESP6500AA

AF:

0.00965

AC:

ESP6500EA

AF:

0.000471

AC:

ExAC

AF:

0.00144

AC:

174

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cone-rod synaptic disorder, congenital nonprogressive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.060

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

0.15

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.24

REVEL

Benign

0.14

Sift

Uncertain

0.011

Sift4G

Benign

0.12

Polyphen

0.062

Vest4

0.097

MVP

0.32

MPC

0.082

ClinPred

0.0083

GERP RS

1.7

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.035

gMVP

0.25

Mutation Taster

=94/6

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over