rs1638565

Variant names:

• chr11-67456450-A-C
• rs1638565
• NM_145200.5:c.541+8A>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 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: 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 305655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CABP4	NM_145200.5	c.541+8A>C		splice_region_variant, intron_variant	Intron 3 of 5	ENST00000325656.7	NP_660201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CABP4	ENST00000325656.7	c.541+8A>C		splice_region_variant, intron_variant	Intron 3 of 5	1	NM_145200.5	ENSP00000324960.5
CABP4	ENST00000438189.6	c.226+8A>C		splice_region_variant, intron_variant	Intron 4 of 6	1		ENSP00000401555.2
CABP4	ENST00000545777.1	n.*197+33A>C		intron_variant	Intron 3 of 3	3		ENSP00000439145.1

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

GnomAD2 exomes AF: 0.429 AC: 105078 AN: 244710 AF XY: 0.411

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 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

African (AFR) AF: 0.820 AC: 27452 AN: 33464

American (AMR) AF: 0.575 AC: 25565 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 8328 AN: 26112

East Asian (EAS) AF: 0.307 AC: 12189 AN: 39666

South Asian (SAS) AF: 0.274 AC: 23586 AN: 86212

European-Finnish (FIN) AF: 0.376 AC: 18134 AN: 48268

Middle Eastern (MID) AF: 0.380 AC: 2186 AN: 5760

European-Non Finnish (NFE) AF: 0.433 AC: 481131 AN: 1111596

Other (OTH) AF: 0.428 AC: 25806 AN: 60322

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

African (AFR) AF: 0.808 AC: 33363 AN: 41302

American (AMR) AF: 0.503 AC: 7667 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1119 AN: 3464

East Asian (EAS) AF: 0.292 AC: 1495 AN: 5114

South Asian (SAS) AF: 0.258 AC: 1245 AN: 4826

European-Finnish (FIN) AF: 0.374 AC: 3930 AN: 10504

Middle Eastern (MID) AF: 0.353 AC: 103 AN: 292

European-Non Finnish (NFE) AF: 0.427 AC: 28954 AN: 67828

Other (OTH) AF: 0.471 AC: 989 AN: 2102

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

Apr 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod synaptic disorder, congenital nonprogressive Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.058
DANN	Benign	0.54
PhyloP100		-5.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1638565; hg19: chr11-67223921; COSMIC: COSV56886609; COSMIC: COSV56886609;