NM_001384732.1:c.94G>A

Variant names:

• chr5-37245833-C-T
• rs73750959
• NM_001384732.1:c.94G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384732.1(CPLANE1):​c.94G>A​(p.Val32Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 1,510,238 control chromosomes in the GnomAD database, including 394 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V32F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (220 hom., cov: 30)
  • Exomes 𝑓: 0.0027 (174 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.56
• Publications: 1 publications found

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, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Illumina
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016393065).
• BP6: Variant 5-37245833-C-T is Benign according to our data. Variant chr5-37245833-C-T is described in ClinVar as Benign. ClinVar VariationId is 158062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0957 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384732.1. 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
	CPLANE1	NM_001384732.1	MANE Select	c.94G>A	p.Val32Ile	missense	Exon 3 of 53	NP_001371661.1	A0A494BZW6
	CPLANE1	NM_023073.4		c.94G>A	p.Val32Ile	missense	Exon 3 of 52	NP_075561.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.94G>A	p.Val32Ile	missense	Exon 3 of 53	ENSP00000498265.2	A0A494BZW6
	CPLANE1	ENST00000955438.1		c.94G>A	p.Val32Ile	missense	Exon 3 of 53	ENSP00000625497.1
	CPLANE1	ENST00000508244.5	TSL:5	c.94G>A	p.Val32Ile	missense	Exon 2 of 51	ENSP00000421690.1	Q9H799-1

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4318 AN: 151952 Hom.: 220 Cov.: 30

Gnomad AFR AF: 0.0983

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.00651 AC: 826 AN: 126950 AF XY: 0.00479

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.00511

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00203

GnomAD4 exome AF: 0.00270 AC: 3671 AN: 1358168 Hom.: 174 Cov.: 31 AF XY: 0.00233 AC XY: 1554 AN XY: 668288

African (AFR) AF: 0.104 AC: 3073 AN: 29578

American (AMR) AF: 0.00591 AC: 161 AN: 27232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23804

East Asian (EAS) AF: 0.0000287 AC: 1 AN: 34828

South Asian (SAS) AF: 0.000288 AC: 20 AN: 69474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48552

Middle Eastern (MID) AF: 0.00192 AC: 8 AN: 4164

European-Non Finnish (NFE) AF: 0.0000545 AC: 58 AN: 1064382

Other (OTH) AF: 0.00623 AC: 350 AN: 56154

GnomAD4 genome AF: 0.0284 AC: 4324 AN: 152070 Hom.: 220 Cov.: 30 AF XY: 0.0273 AC XY: 2031 AN XY: 74336

African (AFR) AF: 0.0982 AC: 4073 AN: 41478

American (AMR) AF: 0.0123 AC: 187 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67978

Other (OTH) AF: 0.0237 AC: 50 AN: 2110

Alfa AF: 0.00996 Hom.: 132

Bravo AF: 0.0335

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.105 AC: 145

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0102 AC: 237

Asia WGS AF: 0.00549 AC: 19 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Joubert syndrome 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0090	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.2	T
PhyloP100		3.6
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.12
Sift	Uncertain	0.017	D
Sift4G	Benign	0.089	T
Vest4		0.14
MPC		0.26
ClinPred		0.022	T
GERP RS		4.3
Varity_R		0.098
gMVP		0.043
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73750959; hg19: chr5-37245935; COSMIC: COSV57077497; COSMIC: COSV57077497;