Genetic Variant CABP4:p.Arg216Gly (chr11-67457677-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145200.5(CABP4):c.646C>G(p.Arg216Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R216Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CABP4
NM_145200.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.21

Publications

0 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: G2P, Labcorp Genetics (formerly Invitae)
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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CABP4	NM_145200.5 link	c.646C>G	p.Arg216Gly	missense_variant	Exon 4 of 6	ENST00000325656.7	NP_660201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CABP4	ENST00000325656.7 link	c.646C>G	p.Arg216Gly	missense_variant	Exon 4 of 6	1	NM_145200.5	ENSP00000324960.5
CABP4	ENST00000438189.6 link	c.331C>G	p.Arg111Gly	missense_variant	Exon 5 of 7	1		ENSP00000401555.2
CABP4	ENST00000545777.1 link	n.*302C>G		downstream_gene_variant		3		ENSP00000439145.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1428704

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32982

American (AMR)

AF:

0.00

AC:

AN:

39374

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25528

East Asian (EAS)

AF:

0.0000262

AC:

AN:

38204

South Asian (SAS)

AF:

0.00

AC:

AN:

81592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50668

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095398

Other (OTH)

AF:

0.00

AC:

AN:

59242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.078

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.0

.;L

PhyloP100

1.2

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Vest4

0.60

ClinPred

1.0

GERP RS

4.6

Varity_R

0.72

gMVP

0.71

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over