11-67521123-C-G

Variant names:

• chr11-67521123-C-G
• rs2276118
• NM_016366.3:c.281G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016366.3(CABP2):​c.281G>C​(p.Arg94Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R94G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: CABP2 NM_016366.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.114
• Publications: 48 publications found

Genes affected

CABP2 (HGNC:1385): (calcium binding protein 2) This gene belongs to a subfamily of calcium binding proteins that share similarity to calmodulin. Like calmodulin, these family members can likely stimulate calmodulin-dependent kinase II and the protein phosphatase calcineurin. Calcium binding proteins are an important component of calcium mediated cellular signal transduction. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

CABP2 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 93

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CABP2	NM_016366.3	c.281G>C	p.Arg94Pro	missense_variant	Exon 4 of 7	ENST00000294288.5	NP_057450.2
CABP2	NM_001318496.2	c.299G>C	p.Arg100Pro	missense_variant	Exon 4 of 7		NP_001305425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CABP2	ENST00000294288.5	c.281G>C	p.Arg94Pro	missense_variant	Exon 4 of 7	1	NM_016366.3	ENSP00000294288.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	-0.0099
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.0	.;L;.
PhyloP100		0.11
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Benign	0.21
Sift	Benign	0.034	D;T;.
Sift4G	Benign	0.082	T;T;.
Vest4		0.56
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.75
gMVP		0.88
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs2276118; hg19: chr11-67288594;