rs1638565

Positions:

• chr11-67456450-A-C
• chr11-67456450-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145200.5(CABP4):​c.541+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,607,472 control chromosomes in the GnomAD database, including 162,284 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23137 hom., cov: 31)
  • Exomes 𝑓: 0.43 (139147 hom.)
• Consequence: CABP4 NM_145200.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001323
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.46

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 11-67456450-A-C is Benign according to our data. Variant chr11-67456450-A-C is described in ClinVar as [Benign]. Clinvar id is 305655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67456450-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABP4	NM_145200.5	c.541+8A>C		splice_region_variant, intron_variant		ENST00000325656.7	NP_660201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CABP4	ENST00000325656.7	c.541+8A>C		splice_region_variant, intron_variant		1	NM_145200.5	ENSP00000324960	P1
CABP4	ENST00000438189.6	c.226+8A>C		splice_region_variant, intron_variant		1		ENSP00000401555
CABP4	ENST00000545777.1	c.*197+33A>C		intron_variant, NMD_transcript_variant		3		ENSP00000439145

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79109 AN: 151468 Hom.: 23100 Cov.: 31

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.359

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.474

GnomAD3 exomes AF: 0.429 AC: 105078 AN: 244710 Hom.: 24695 AF XY: 0.411 AC XY: 54567 AN XY: 132920

Gnomad AFR exome AF: 0.814

Gnomad AMR exome AF: 0.578

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.284

Gnomad SAS exome AF: 0.268

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.417

Gnomad OTH exome AF: 0.415

GnomAD4 exome AF: 0.429 AC: 624377 AN: 1455884 Hom.: 139147 Cov.: 59 AF XY: 0.421 AC XY: 304878 AN XY: 724226

Gnomad4 AFR exome AF: 0.820

Gnomad4 AMR exome AF: 0.575

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.307

Gnomad4 SAS exome AF: 0.274

Gnomad4 FIN exome AF: 0.376

Gnomad4 NFE exome AF: 0.433

Gnomad4 OTH exome AF: 0.428

GnomAD4 genome AF: 0.522 AC: 79192 AN: 151588 Hom.: 23137 Cov.: 31 AF XY: 0.511 AC XY: 37851 AN XY: 74038

Gnomad4 AFR AF: 0.808

Gnomad4 AMR AF: 0.503

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.292

Gnomad4 SAS AF: 0.258

Gnomad4 FIN AF: 0.374

Gnomad4 NFE AF: 0.427

Gnomad4 OTH AF: 0.471

Alfa AF: 0.363 Hom.: 2009

Bravo AF: 0.551

Asia WGS AF: 0.353 AC: 1228 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cone-rod synaptic disorder, congenital nonprogressive Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.058
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
SpliceAI score (max)		0.030		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: rs1638565; hg19: chr11-67223921; COSMIC: COSV56886609; COSMIC: COSV56886609;