Genetic Variant CNBD2:p.Pro178Leu (chr20-35984107-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001365709.1(CNBD2):c.533C>T(p.Pro178Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,459,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

CNBD2
NM_001365709.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.39

Variant links:

Genes affected

CNBD2 (HGNC:16145): (cyclic nucleotide binding domain containing 2) Predicted to enable cAMP binding activity. Predicted to be involved in spermatogenesis. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

CNBD2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNBD2	NM_001365709.1 link	c.533C>T	p.Pro178Leu	missense_variant	Exon 5 of 12	ENST00000373973.7	NP_001352638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNBD2	ENST00000373973.7 link	c.533C>T	p.Pro178Leu	missense_variant	Exon 5 of 12	5	NM_001365709.1	ENSP00000363084.3	Q96M20-1
CNBD2	ENST00000538900.1 link	c.533C>T	p.Pro178Leu	missense_variant	Exon 5 of 11	1		ENSP00000442729.1	Q96M20-3
CNBD2	ENST00000463258.6 link	n.408-520C>T		intron_variant	Intron 4 of 8	1		ENSP00000476014.1	U3KQM1
CNBD2	ENST00000349339.5 link	c.533C>T	p.Pro178Leu	missense_variant	Exon 5 of 12	2		ENSP00000340954.1	Q96M20-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248316

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

134148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1459570

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.533C>T (p.P178L) alteration is located in exon 5 (coding exon 5) of the CNBD2 gene. This alteration results from a C to T substitution at nucleotide position 533, causing the proline (P) at amino acid position 178 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Uncertain

0.067

MutationAssessor

Uncertain

2.3

M;M;M

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.010

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.80

MutPred

0.43

Loss of disorder (P = 0.0229);Loss of disorder (P = 0.0229);Loss of disorder (P = 0.0229);

MVP

0.77

MPC

0.46

ClinPred

0.99

GERP RS

5.5

Varity_R

0.17

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over