11-67455397-G-A

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CABP4	NM_145200.5	c.-27G>A		5_prime_UTR_variant	Exon 1 of 6	ENST00000325656.7	NP_660201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CABP4	ENST00000325656	c.-27G>A		5_prime_UTR_variant	Exon 1 of 6	1	NM_145200.5	ENSP00000324960.5

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

GnomAD3 exomes AF: 0.00199 AC: 459 AN: 230284 Hom.: 2 AF XY: 0.00218 AC XY: 275 AN XY: 126236

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 SAS exome AF: 0.00296

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

Gnomad4 AFR exome AF: 0.0000921

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00113

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00302

Gnomad4 FIN exome AF: 0.00949

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.00140

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

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000684

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cone-rod synaptic disorder, congenital nonprogressive Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.078
DANN	Benign	0.49

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

LitVar

Other links and lift over

dbSNP: rs192302421; hg19: chr11-67222868;