chr11-67455397-G-A

Variant names:

• chr11-67455397-G-A
• rs192302421
• NM_145200.5:c.-27G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_145200.5(CABP4):​c.-27G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,591,160 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (13 hom.)
• Consequence: CABP4 NM_145200.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.29
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00169 (257/152312) while in subpopulation SAS AF = 0.00269 (13/4826). AF 95% confidence interval is 0.00159. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABP4	NM_145200.5	MANE Select	c.-27G>A		5_prime_UTR	Exon 1 of 6	NP_660201.1	P57796-1
	CABP4	NM_001300895.3		c.-410G>A		5_prime_UTR	Exon 1 of 6	NP_001287824.1	P57796-2
	CABP4	NM_001300896.3		c.-112-312G>A		intron	N/A	NP_001287825.1	P57796-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABP4	ENST00000325656.7	TSL:1 MANE Select	c.-27G>A		5_prime_UTR	Exon 1 of 6	ENSP00000324960.5	P57796-1
	CABP4	ENST00000438189.6	TSL:1	c.-112-312G>A		intron	N/A	ENSP00000401555.2	P57796-2
	CABP4	ENST00000538060.1	TSL:4	n.296-37G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152194 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00199 AC: 459 AN: 230284 AF XY: 0.00218

Gnomad AFR exome AF: 0.000136

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.000585

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00964

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00159 AC: 2281 AN: 1438848 Hom.: 13 Cov.: 31 AF XY: 0.00167 AC XY: 1189 AN XY: 714064

African (AFR) AF: 0.0000921 AC: 3 AN: 32584

American (AMR) AF: 0.000336 AC: 14 AN: 41646

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 28 AN: 24790

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.00302 AC: 253 AN: 83854

European-Finnish (FIN) AF: 0.00949 AC: 490 AN: 51610

Middle Eastern (MID) AF: 0.00378 AC: 17 AN: 4496

European-Non Finnish (NFE) AF: 0.00126 AC: 1393 AN: 1101230

Other (OTH) AF: 0.00140 AC: 83 AN: 59166

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152312 Hom.: 2 Cov.: 33 AF XY: 0.00226 AC XY: 168 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41574

American (AMR) AF: 0.000327 AC: 5 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.0126 AC: 134 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 68010

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000684

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cone-rod synaptic disorder, congenital nonprogressive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.078
DANN	Benign	0.49
PhyloP100		-2.3
PromoterAI		0.0020	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs192302421; hg19: chr11-67222868;