Genetic Variant NM_182511.4: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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182511.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBLN2	NM_182511.4	MANE Select	c.-166-135C>A		intron	N/A	NP_872317.1	Q8IUK8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CBLN2	ENST00000269503.9	TSL:1 MANE Select	c.-166-135C>A	intron	N/A	ENSP00000269503.4	Q8IUK8
CBLN2	ENST00000585159.5	TSL:1	c.-166-135C>A	intron	N/A	ENSP00000463771.1	Q8IUK8
CBLN2	ENST00000881350.1		c.-301C>A	5_prime_UTR	Exon 1 of 3	ENSP00000551409.1

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

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over