11-67455476-G-A

Position:

• chr11-67455476-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145200.5(CABP4):​c.53G>A​(p.Arg18His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000928 in 1,610,720 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (3 hom.)
• Consequence: CABP4 NM_145200.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.155

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 (MetaRNN=0.0071252286).
• BP6: Variant 11-67455476-G-A is Benign according to our data. Variant chr11-67455476-G-A is described in ClinVar as [Benign]. Clinvar id is 305639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67455476-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00379 (577/152322) while in subpopulation AFR AF= 0.0124 (514/41578). AF 95% confidence interval is 0.0115. There are 5 homozygotes in gnomad4. There are 273 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABP4	NM_145200.5	c.53G>A	p.Arg18His	missense_variant	1/6	ENST00000325656.7	NP_660201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CABP4	ENST00000325656.7	c.53G>A	p.Arg18His	missense_variant	1/6	1	NM_145200.5	ENSP00000324960	P1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 573 AN: 152204 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00153 AC: 365 AN: 239230 Hom.: 2 AF XY: 0.00144 AC XY: 188 AN XY: 130962

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.00100

Gnomad ASJ exome AF: 0.00729

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00171

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000629 AC: 918 AN: 1458398 Hom.: 3 Cov.: 31 AF XY: 0.000655 AC XY: 475 AN XY: 725268

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.00755

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00188

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00379 AC: 577 AN: 152322 Hom.: 5 Cov.: 33 AF XY: 0.00367 AC XY: 273 AN XY: 74488

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000929 Hom.: 0

Bravo AF: 0.00416

ESP6500AA AF: 0.00965 AC: 42

ESP6500EA AF: 0.000471 AC: 4

ExAC AF: 0.00144 AC: 174

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	- -

Cone-rod synaptic disorder, congenital nonprogressive Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.90
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.14
Sift	Uncertain	0.011	D
Sift4G	Benign	0.12	T
Polyphen		0.062	B
Vest4		0.097
MVP		0.32
MPC		0.082
ClinPred		0.0083	T
GERP RS		1.7
Varity_R		0.035
gMVP		0.25

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: rs140245752; hg19: chr11-67222947;