Genetic Variant COBLL1:p.Asn901Asp (chr2-164694691-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001365672.2(COBLL1):c.2701A>G(p.Asn901Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,602 control chromosomes in the GnomAD database, including 11,983 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.13 ( 1281 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10702 hom. )

Consequence

COBLL1
NM_001365672.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.685

Publications

83 publications found

Variant links:

Genes affected

COBLL1 (HGNC:23571): (cordon-bleu WH2 repeat protein like 1) Enables cadherin binding activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

COBLL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001427412).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COBLL1	NM_001365672.2 link	c.2701A>G	p.Asn901Asp	missense_variant	Exon 12 of 14	ENST00000652658.2	NP_001352601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COBLL1	ENST00000652658.2 link	c.2701A>G	p.Asn901Asp	missense_variant	Exon 12 of 14		NM_001365672.2	ENSP00000498242.1

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19173

AN:

151800

Hom.:

1281

Cov.:

show subpopulations

Gnomad AFR

AF:

0.157

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.114

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.102

Gnomad FIN

AF:

0.0860

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.129

GnomAD2 exomes

AF:

0.108

AC:

27042

AN:

250474

AF XY:

0.111

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.0712

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.0939

Gnomad NFE exome

AF:

0.127

Gnomad OTH exome

AF:

0.129

GnomAD4 exome

AF:

0.118

AC:

172098

AN:

1461684

Hom.:

10702

Cov.:

AF XY:

0.118

AC XY:

86143

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.159

AC:

5331

AN:

33468

American (AMR)

AF:

0.0747

AC:

3335

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

3834

AN:

26126

East Asian (EAS)

AF:

0.000302

AC:

AN:

39698

South Asian (SAS)

AF:

0.109

AC:

9426

AN:

86250

European-Finnish (FIN)

AF:

0.0983

AC:

5247

AN:

53392

Middle Eastern (MID)

AF:

0.170

AC:

981

AN:

5756

European-Non Finnish (NFE)

AF:

0.123

AC:

136570

AN:

1111932

Other (OTH)

AF:

0.122

AC:

7362

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

9207

18414

27620

36827

46034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4862

9724

14586

19448

24310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.126

AC:

19178

AN:

151918

Hom.:

1281

Cov.:

AF XY:

0.125

AC XY:

9292

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.157

AC:

6497

AN:

41414

American (AMR)

AF:

0.114

AC:

1729

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

523

AN:

3466

East Asian (EAS)

AF:

0.00155

AC:

AN:

5164

South Asian (SAS)

AF:

0.101

AC:

484

AN:

4806

European-Finnish (FIN)

AF:

0.0860

AC:

910

AN:

10576

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.127

AC:

8608

AN:

67956

Other (OTH)

AF:

0.128

AC:

270

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

840

1679

2519

3358

4198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.125

Hom.:

5993

Bravo

AF:

0.129

TwinsUK

AF:

0.119

AC:

442

ALSPAC

AF:

0.131

AC:

504

ESP6500AA

AF:

0.156

AC:

687

ESP6500EA

AF:

0.125

AC:

1074

ExAC

AF:

0.110

AC:

13349

Asia WGS

AF:

0.0570

AC:

197

AN:

3478

EpiCase

AF:

0.130

EpiControl

AF:

0.131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.4

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.032

T;.;.;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.36

T;T;T;T

MetaRNN

Benign

0.0014

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;.;.

PhyloP100

0.69

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.6

N;N;N;.

REVEL

Benign

0.040

Sift

Benign

0.13

T;T;T;.

Sift4G

Benign

0.31

T;T;T;T

Polyphen

0.70

P;.;.;.

Vest4

0.054

MPC

0.063

ClinPred

0.0070

GERP RS

-2.6

Varity_R

0.093

gMVP

0.089

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over