11-67456450-A-C

Variant names:

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

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: 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 -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.

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.541+8A>C		splice_region intron	N/A	NP_660201.1	P57796-1
	CABP4	NM_001300895.3		c.226+8A>C		splice_region intron	N/A	NP_001287824.1	P57796-2
	CABP4	NM_001300896.3		c.226+8A>C		splice_region 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.541+8A>C		splice_region intron	N/A	ENSP00000324960.5	P57796-1
	CABP4	ENST00000438189.6	TSL:1	c.226+8A>C		splice_region intron	N/A	ENSP00000401555.2	P57796-2
	CABP4	ENST00000545777.1	TSL:3	n.*197+33A>C		intron	N/A	ENSP00000439145.1	F5H3E8

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Cone-rod synaptic disorder, congenital nonprogressive (2)

Computational scores

Source: dbNSFP v4.9

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;