5-37153938-T-G

Variant names:

• chr5-37153938-T-G
• rs201122718
• NM_001384732.1:c.8175A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001384732.1(CPLANE1):​c.8175A>C​(p.Ala2725Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,614,132 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: CPLANE1 NM_001384732.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.16
• Publications: 0 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, 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-37153938-T-G is Benign according to our data. Variant chr5-37153938-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261676.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000394 (60/152328) while in subpopulation AMR AF = 0.00137 (21/15304). AF 95% confidence interval is 0.000919. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.8175A>C	p.Ala2725Ala	synonymous	Exon 42 of 53	NP_001371661.1
	CPLANE1	NM_023073.4		c.8013A>C	p.Ala2671Ala	synonymous	Exon 41 of 52	NP_075561.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.8175A>C	p.Ala2725Ala	synonymous	Exon 42 of 53	ENSP00000498265.2
	CPLANE1	ENST00000514429.5	TSL:1	c.5211A>C	p.Ala1737Ala	synonymous	Exon 26 of 37	ENSP00000424223.1
	CPLANE1	ENST00000509849.5	TSL:1	n.5187A>C		non_coding_transcript_exon	Exon 27 of 37	ENSP00000426337.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000485 AC: 122 AN: 251354 AF XY: 0.000464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00575

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000268 AC: 392 AN: 1461804 Hom.: 2 Cov.: 31 AF XY: 0.000241 AC XY: 175 AN XY: 727202

African (AFR) AF: 0.000149 AC: 5 AN: 33470

American (AMR) AF: 0.000694 AC: 31 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00524 AC: 137 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5768

European-Non Finnish (NFE) AF: 0.0000971 AC: 108 AN: 1111970

Other (OTH) AF: 0.000844 AC: 51 AN: 60394

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74494

African (AFR) AF: 0.0000722 AC: 3 AN: 41574

American (AMR) AF: 0.00137 AC: 21 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.000495

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.40
DANN	Benign	0.25
PhyloP100		-1.2
Mutation Taster		=100/0	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: rs201122718; hg19: chr5-37154040;