Genetic Variant NM_001384732.1:c.336C>A (chr5-37245480-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001384732.1(CPLANE1):c.336C>A(p.Val112Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,283,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. V112V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

CPLANE1
NM_001384732.1 splice_region, synonymous

Scores

Splicing: ADA: 0.0001852

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.66

Publications

0 publications found

Variant links:

Genes affected

CPLANE1 (HGNC:25801): (ciliogenesis and planar polarity effector complex subunit 1) The protein encoded by this gene has putative coiled-coil domains and may be a transmembrane protein. Defects in this gene are a cause of Joubert syndrome (JBTS). [provided by RefSeq, May 2012]

CPLANE1 Gene-Disease associations (from GenCC):

Joubert syndrome 17
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, G2P, Illumina, Labcorp Genetics (formerly Invitae)
orofaciodigital syndrome type 6
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CPLANE1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLANE1	NM_001384732.1 link	c.336C>A	p.Val112Val	splice_region_variant, synonymous_variant	Exon 4 of 53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPLANE1	ENST00000651892.2 link	c.336C>A	p.Val112Val	splice_region_variant, synonymous_variant	Exon 4 of 53		NM_001384732.1	ENSP00000498265.2	A0A494BZW6
CPLANE1	ENST00000508244.5 link	c.336C>A	p.Val112Val	splice_region_variant, synonymous_variant	Exon 3 of 51	5		ENSP00000421690.1	Q9H799-1
CPLANE1	ENST00000425232.7 link	n.117C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 30	5		ENSP00000389014.3	A0A7I2XYG4
CPLANE1	ENST00000675547.1 link	n.639C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 15

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000156

AC:

AN:

1283136

Hom.:

Cov.:

AF XY:

0.00000160

AC XY:

AN XY:

626330

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27212

American (AMR)

AF:

0.00

AC:

AN:

19596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21422

East Asian (EAS)

AF:

0.00

AC:

AN:

31874

South Asian (SAS)

AF:

0.0000172

AC:

AN:

58208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5254

European-Non Finnish (NFE)

AF:

9.80e-7

AC:

AN:

1020672

Other (OTH)

AF:

0.00

AC:

AN:

52576

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.094

SpliceAI score (max)

0.76

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.76

Position offset: 3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over