rs121917828

Variant names:

• chr11-67456191-C-G
• rs121917828
• NM_145200.5:c.370C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-67456191-C-G
• chr11-67456191-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_145200.5(CABP4):​c.370C>G​(p.Arg124Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,100 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R124C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CABP4 NM_145200.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.510
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-67456191-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1953.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABP4	NM_145200.5	MANE Select	c.370C>G	p.Arg124Gly	missense	Exon 2 of 6	NP_660201.1
	CABP4	NM_001300895.3		c.55C>G	p.Arg19Gly	missense	Exon 2 of 6	NP_001287824.1
	CABP4	NM_001300896.3		c.55C>G	p.Arg19Gly	missense	Exon 3 of 7	NP_001287825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABP4	ENST00000325656.7	TSL:1 MANE Select	c.370C>G	p.Arg124Gly	missense	Exon 2 of 6	ENSP00000324960.5
	CABP4	ENST00000438189.6	TSL:1	c.55C>G	p.Arg19Gly	missense	Exon 3 of 7	ENSP00000401555.2
	CABP4	ENST00000545777.1	TSL:3	n.*51C>G		non_coding_transcript_exon	Exon 2 of 4	ENSP00000439145.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461100 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726870

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.51
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.30		Loss of ubiquitination at K122 (P = 0.1224)
MVP		0.62
MPC		0.46
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.73
gMVP		0.69
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121917828; hg19: chr11-67223662;