Genetic Variant CBLN2:c.-166-135C>A (chr18-72542461-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_182511.4(CBLN2):c.-166-135C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.008 in 184,812 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 14 hom., cov: 31)

Exomes 𝑓: 0.0065 ( 1 hom. )

Consequence

CBLN2
NM_182511.4 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.671

Publications

1 publications found

Variant links:

Genes affected

CBLN2 (HGNC:1544): (cerebellin 2 precursor) Predicted to be involved in maintenance of synapse structure and spontaneous synaptic transmission. Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be located in extracellular space. Predicted to be active in glutamatergic synapse. [provided by Alliance of Genome Resources, Apr 2022]

CBLN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 18-72542461-G-T is Benign according to our data. Variant chr18-72542461-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1316642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00832 (1265/151966) while in subpopulation SAS AF = 0.0394 (189/4800). AF 95% confidence interval is 0.0348. There are 14 homozygotes in GnomAd4. There are 647 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLN2	NM_182511.4 link	c.-166-135C>A		intron_variant	Intron 2 of 4	ENST00000269503.9	NP_872317.1	Q8IUK8A0A024R380

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLN2	ENST00000269503.9 link	c.-166-135C>A		intron_variant	Intron 2 of 4	1	NM_182511.4	ENSP00000269503.4		Q8IUK8

Frequencies

GnomAD3 genomes

AF:

0.00832

AC:

1264

AN:

151848

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00917

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.0228

Gnomad SAS

AF:

0.0391

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00977

Gnomad OTH

AF:

0.00814

GnomAD4 exome

AF:

0.00652

AC:

214

AN:

32846

Hom.:

AF XY:

0.00616

AC XY:

107

AN XY:

17358

show subpopulations

African (AFR)

AF:

0.00391

AC:

AN:

768

American (AMR)

AF:

0.00629

AC:

AN:

954

Ashkenazi Jewish (ASJ)

AF:

0.00523

AC:

AN:

1148

East Asian (EAS)

AF:

0.0172

AC:

AN:

1048

South Asian (SAS)

AF:

0.0317

AC:

AN:

284

European-Finnish (FIN)

AF:

0.000303

AC:

AN:

3304

Middle Eastern (MID)

AF:

0.00562

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.00693

AC:

160

AN:

23104

Other (OTH)

AF:

0.00486

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00832

AC:

1265

AN:

151966

Hom.:

Cov.:

AF XY:

0.00871

AC XY:

647

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00246

AC:

102

AN:

41462

American (AMR)

AF:

0.00916

AC:

140

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3466

East Asian (EAS)

AF:

0.0233

AC:

118

AN:

5074

South Asian (SAS)

AF:

0.0394

AC:

189

AN:

4800

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00977

AC:

664

AN:

67966

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

142

212

283

354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00907

Hom.:

Bravo

AF:

0.00745

Asia WGS

AF:

0.0310

AC:

107

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 30, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

4.1

(source)

DANN

Benign

0.83

PhyloP100

0.67

Mutation Taster

=100/0

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over