Genetic Variant NM_015198.5:c.3628C>A (chr7-51025249-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015198.5(COBL):c.3628C>A(p.Pro1210Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

COBL
NM_015198.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.937

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13605928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COBL	NM_015198.5 link	c.3628C>A	p.Pro1210Thr	missense_variant	Exon 12 of 13	ENST00000265136.12	NP_056013.2	O75128-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COBL	ENST00000265136.12 link	c.3628C>A	p.Pro1210Thr	missense_variant	Exon 12 of 13	1	NM_015198.5	ENSP00000265136.7		O75128-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151204

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000413

AC:

AN:

242162

Hom.:

AF XY:

0.00000753

AC XY:

AN XY:

132718

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000132

AC:

AN:

151204

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73802

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.48

CADD

Benign

9.5

DANN

Benign

0.94

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;L

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.042

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

0.51

.;P

Vest4

0.23

MutPred

0.27

.;Gain of phosphorylation at P1210 (P = 0.0042);

MVP

0.35

MPC

0.070

ClinPred

0.22

GERP RS

1.6

Varity_R

0.078

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over