rs74975451

Variant names:

• chr5-37226712-C-T
• rs74975451
• NM_001384732.1:c.1883G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384732.1(CPLANE1):​c.1883G>A​(p.Arg628Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,547,190 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (26 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.695
• Publications: 5 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=0.0026712418).
• BP6: Variant 5-37226712-C-T is Benign according to our data. Variant chr5-37226712-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00119 (181/152244) while in subpopulation EAS AF = 0.0322 (167/5188). AF 95% confidence interval is 0.0282. There are 4 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.1883G>A	p.Arg628Lys	missense	Exon 12 of 53	NP_001371661.1	A0A494BZW6
	CPLANE1	NM_023073.4		c.1883G>A	p.Arg628Lys	missense	Exon 12 of 52	NP_075561.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.1883G>A	p.Arg628Lys	missense	Exon 12 of 53	ENSP00000498265.2	A0A494BZW6
	CPLANE1	ENST00000955438.1		c.1883G>A	p.Arg628Lys	missense	Exon 12 of 53	ENSP00000625497.1
	CPLANE1	ENST00000508244.5	TSL:5	c.1883G>A	p.Arg628Lys	missense	Exon 11 of 51	ENSP00000421690.1	Q9H799-1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152126 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00268 AC: 409 AN: 152500 AF XY: 0.00257

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0348

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000337

Gnomad OTH exome AF: 0.000933

GnomAD4 exome AF: 0.00102 AC: 1422 AN: 1394946 Hom.: 26 Cov.: 32 AF XY: 0.00102 AC XY: 700 AN XY: 687448

African (AFR) AF: 0.0000318 AC: 1 AN: 31402

American (AMR) AF: 0.000143 AC: 5 AN: 35004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25048

East Asian (EAS) AF: 0.0343 AC: 1221 AN: 35640

South Asian (SAS) AF: 0.00108 AC: 84 AN: 77962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49222

Middle Eastern (MID) AF: 0.000882 AC: 5 AN: 5672

European-Non Finnish (NFE) AF: 0.0000269 AC: 29 AN: 1077170

Other (OTH) AF: 0.00133 AC: 77 AN: 57826

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152244 Hom.: 4 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74438

African (AFR) AF: 0.00 AC: 0 AN: 41536

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0322 AC: 167 AN: 5188

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.00147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00119 AC: 29

Asia WGS AF: 0.00838 AC: 29 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	0.083
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.33
DANN	Benign	0.65
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0027	T
MetaSVM	Uncertain	-0.24	T
PhyloP100		0.69
PROVEAN	Benign	0.23	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.030
MVP		0.36
MPC		0.12
ClinPred		0.0020	T
GERP RS		-3.0
Varity_R		0.036
gMVP		0.037
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs74975451; hg19: chr5-37226814; COSMIC: COSV107276234;