chr5-37180915-T-C

Variant names:

• chr5-37180915-T-C
• rs76245173
• NM_001384732.1:c.5512A>G

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.5512A>G​(p.Thr1838Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,613,928 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (57 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (76 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.24
• Publications: 10 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=0.0025082827).
• BP6: Variant 5-37180915-T-C is Benign according to our data. Variant chr5-37180915-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0506 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.5512A>G	p.Thr1838Ala	missense	Exon 27 of 53	NP_001371661.1	A0A494BZW6
	CPLANE1	NM_023073.4		c.5512A>G	p.Thr1838Ala	missense	Exon 27 of 52	NP_075561.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.5512A>G	p.Thr1838Ala	missense	Exon 27 of 53	ENSP00000498265.2	A0A494BZW6
	CPLANE1	ENST00000514429.5	TSL:1	c.2656A>G	p.Thr886Ala	missense	Exon 12 of 37	ENSP00000424223.1	H0Y9I8
	CPLANE1	ENST00000509849.5	TSL:1	n.2527A>G		non_coding_transcript_exon	Exon 12 of 37	ENSP00000426337.1	H0YA77

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2615 AN: 152126 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00826

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.00730 AC: 1836 AN: 251404 AF XY: 0.00699

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00479 AC: 6998 AN: 1461684 Hom.: 76 Cov.: 30 AF XY: 0.00498 AC XY: 3620 AN XY: 727152

African (AFR) AF: 0.0563 AC: 1884 AN: 33470

American (AMR) AF: 0.00570 AC: 255 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0102 AC: 876 AN: 86252

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53400

Middle Eastern (MID) AF: 0.0220 AC: 127 AN: 5766

European-Non Finnish (NFE) AF: 0.00306 AC: 3403 AN: 1111866

Other (OTH) AF: 0.00719 AC: 434 AN: 60388

GnomAD4 genome AF: 0.0172 AC: 2619 AN: 152244 Hom.: 57 Cov.: 32 AF XY: 0.0169 AC XY: 1256 AN XY: 74440

African (AFR) AF: 0.0524 AC: 2177 AN: 41526

American (AMR) AF: 0.00825 AC: 126 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00934 AC: 45 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00331 AC: 225 AN: 68020

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.00786 Hom.: 42

Bravo AF: 0.0199

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0561 AC: 247

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00847 AC: 1029

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00640

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Joubert syndrome 17 (1)
-	-	1	Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.010
DANN	Benign	0.12
DEOGEN2	Benign	0.011	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.2
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.048
Sift	Benign	1.0	T
Sift4G	Benign	0.96	T
Vest4		0.092
MVP		0.014
MPC		0.12
ClinPred		0.0034	T
GERP RS		-12
Varity_R		0.032
gMVP		0.34
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs76245173; hg19: chr5-37181017;