NM_016366.3:c.281G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016366.3(CABP2):​c.281G>A​(p.Arg94Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,612,864 control chromosomes in the GnomAD database, including 247,091 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.43 (17502 hom., cov: 29)
  • Exomes 𝑓: 0.55 (229589 hom.)
• Consequence: CABP2 NM_016366.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.3817655E-6).
• BP6: Variant 11-67521123-C-T is Benign according to our data. Variant chr11-67521123-C-T is described in ClinVar as Benign. ClinVar VariationId is 506033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016366.3. 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
	CABP2	NM_016366.3	MANE Select	c.281G>A	p.Arg94Gln	missense	Exon 4 of 7	NP_057450.2
	CABP2	NM_001318496.2		c.299G>A	p.Arg100Gln	missense	Exon 4 of 7	NP_001305425.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CABP2	ENST00000294288.5	TSL:1 MANE Select	c.281G>A	p.Arg94Gln	missense	Exon 4 of 7	ENSP00000294288.4
	CABP2	ENST00000545205.2	TSL:1	n.*66G>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000446180.1
	CABP2	ENST00000545205.2	TSL:1	n.*66G>A		3_prime_UTR	Exon 4 of 7	ENSP00000446180.1

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65787 AN: 151606 Hom.: 17497 Cov.: 29

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.482

GnomAD2 exomes AF: 0.529 AC: 132663 AN: 250936 AF XY: 0.547

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.674

Gnomad EAS exome AF: 0.696

Gnomad FIN exome AF: 0.541

Gnomad NFE exome AF: 0.568

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.553 AC: 808562 AN: 1461140 Hom.: 229589 Cov.: 49 AF XY: 0.559 AC XY: 406332 AN XY: 726896

African (AFR) AF: 0.0938 AC: 3141 AN: 33480

American (AMR) AF: 0.371 AC: 16580 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 17693 AN: 26134

East Asian (EAS) AF: 0.676 AC: 26853 AN: 39698

South Asian (SAS) AF: 0.635 AC: 54735 AN: 86244

European-Finnish (FIN) AF: 0.541 AC: 28609 AN: 52880

Middle Eastern (MID) AF: 0.565 AC: 3259 AN: 5768

European-Non Finnish (NFE) AF: 0.562 AC: 624725 AN: 1111834

Other (OTH) AF: 0.546 AC: 32967 AN: 60390

GnomAD4 genome AF: 0.434 AC: 65789 AN: 151724 Hom.: 17502 Cov.: 29 AF XY: 0.441 AC XY: 32647 AN XY: 74102

African (AFR) AF: 0.110 AC: 4537 AN: 41378

American (AMR) AF: 0.439 AC: 6689 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2352 AN: 3464

East Asian (EAS) AF: 0.682 AC: 3501 AN: 5132

South Asian (SAS) AF: 0.642 AC: 3078 AN: 4792

European-Finnish (FIN) AF: 0.538 AC: 5670 AN: 10540

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38245 AN: 67878

Other (OTH) AF: 0.487 AC: 1024 AN: 2104

Alfa AF: 0.532 Hom.: 99716

Bravo AF: 0.409

TwinsUK AF: 0.563 AC: 2089

ALSPAC AF: 0.569 AC: 2193

ESP6500AA AF: 0.127 AC: 558

ESP6500EA AF: 0.568 AC: 4879

ExAC AF: 0.528 AC: 64121

Asia WGS AF: 0.598 AC: 2075 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg94Gln in exon 4 of CABP2: This variant is not expected to have clinical sig nificance because it has been identified in 69.33% (5982/8628) of East Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs2276118).

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 93 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0000034	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.11
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.057
Sift	Benign	0.30	T
Sift4G	Benign	0.34	T
Polyphen		0.27	B
Vest4		0.051
MPC		0.36
ClinPred		0.010	T
GERP RS		3.6
Varity_R		0.069
gMVP		0.40
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV53709797;