Genetic Variant COBL:p.Ala1237Thr (chr7-51025168-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015198.5(COBL):c.3709G>A(p.Ala1237Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000129 in 1,544,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

COBL
NM_015198.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.22

Publications

0 publications found

Variant links:

Genes affected

COBL (HGNC:22199): (cordon-bleu WH2 repeat protein) This gene encodes a protein that contains WH2 domains (WASP, Wiskott-Aldrich syndrome protein, homology domain-2) that interact with actin. The encoded actin regulator protein is required for growth and assembly of brush border microvilli that play a role in maintaining intestinal homeostasis. A similar protein in mouse functions in midbrain neural tube closure. A pseudogene of this gene is located on chromosome X. [provided by RefSeq, Oct 2016]

COBL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015198.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COBL	NM_015198.5	MANE Select	c.3709G>A	p.Ala1237Thr	missense	Exon 12 of 13	NP_056013.2
COBL	NM_001410881.1		c.3955G>A	p.Ala1319Thr	missense	Exon 14 of 15	NP_001397810.1	O75128-2
COBL	NM_001287436.3		c.3739G>A	p.Ala1247Thr	missense	Exon 13 of 14	NP_001274365.1	O75128-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COBL	ENST00000265136.12	TSL:1 MANE Select	c.3709G>A	p.Ala1237Thr	missense	Exon 12 of 13	ENSP00000265136.7	O75128-1
COBL	ENST00000431948.6	TSL:1	c.3955G>A	p.Ala1319Thr	missense	Exon 14 of 15	ENSP00000413498.2	O75128-2
COBL	ENST00000395542.6	TSL:1	c.3739G>A	p.Ala1247Thr	missense	Exon 13 of 14	ENSP00000378912.3	O75128-7

Frequencies

GnomAD3 genomes

AF:

0.0000408

AC:

AN:

147230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000270

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249486

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1397764

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

694668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31526

American (AMR)

AF:

0.00

AC:

AN:

42760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23814

East Asian (EAS)

AF:

0.00

AC:

AN:

34408

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85544

European-Finnish (FIN)

AF:

0.0000206

AC:

AN:

48648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3846

European-Non Finnish (NFE)

AF:

0.0000103

AC:

AN:

1071204

Other (OTH)

AF:

0.00

AC:

AN:

56014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000408

AC:

AN:

147230

Hom.:

Cov.:

AF XY:

0.0000558

AC XY:

AN XY:

71676

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40586

American (AMR)

AF:

0.000270

AC:

AN:

14826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.00

AC:

AN:

4608

South Asian (SAS)

AF:

0.00

AC:

AN:

4284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66520

Other (OTH)

AF:

0.00

AC:

AN:

2038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000282

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.0

PhyloP100

4.2

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.3

REVEL

Benign

0.22

Sift

Benign

0.060

Sift4G

Benign

0.10

Polyphen

1.0

Vest4

0.43

MutPred

0.64

Gain of glycosylation at A1237 (P = 0.0434)

MVP

0.52

MPC

0.36

ClinPred

0.83

GERP RS

5.6

Varity_R

0.11

gMVP

0.64

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over