rs113941736

Variant names:

• chr7-130400746-A-C
• rs113941736
• NM_018718.3:c.718T>G

Variant summary

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

The NM_018718.3(CEP41):​c.718T>G​(p.Cys240Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,780 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. C240C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (16 hom.)
• Consequence: CEP41 NM_018718.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.36
• Publications: 5 publications found

Genes affected

CEP41 (HGNC:12370): (centrosomal protein 41) This gene encodes a centrosomal and microtubule-binding protein which is predicted to have two coiled-coil domains and a rhodanese domain. In human retinal pigment epithelial cells the protein localized to centrioles and cilia. Mutations in this gene have been associated with Joubert Syndrome 15; an autosomal recessive ciliopathy and neurological disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

CEP41 Gene-Disease associations (from GenCC):

• Joubert syndrome 15

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  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=0.010561943).
• BP6: Variant 7-130400746-A-C is Benign according to our data. Variant chr7-130400746-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00693 (1056/152324) while in subpopulation AFR AF = 0.0243 (1009/41582). AF 95% confidence interval is 0.023. There are 10 homozygotes in GnomAd4. There are 458 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018718.3. 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
	CEP41	NM_018718.3	MANE Select	c.718T>G	p.Cys240Gly	missense	Exon 9 of 11	NP_061188.1	Q9BYV8-1
	CEP41	NM_001257158.2		c.718T>G	p.Cys240Gly	missense	Exon 9 of 10	NP_001244087.1	Q9BYV8-2
	CEP41	NM_001257159.2		c.670T>G	p.Cys224Gly	missense	Exon 8 of 9	NP_001244088.1	Q9BYV8-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP41	ENST00000223208.10	TSL:1 MANE Select	c.718T>G	p.Cys240Gly	missense	Exon 9 of 11	ENSP00000223208.4	Q9BYV8-1
	CEP41	ENST00000343969.10	TSL:1	c.718T>G	p.Cys240Gly	missense	Exon 9 of 10	ENSP00000342738.6	A0A7I2PK71
	CEP41	ENST00000484549.6	TSL:1	n.*890T>G		non_coding_transcript_exon	Exon 9 of 11	ENSP00000419078.2	C9IZ34

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1055 AN: 152206 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00166 AC: 417 AN: 250872 AF XY: 0.00111

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000738 AC: 1079 AN: 1461456 Hom.: 16 Cov.: 30 AF XY: 0.000659 AC XY: 479 AN XY: 726994

African (AFR) AF: 0.0278 AC: 932 AN: 33470

American (AMR) AF: 0.000805 AC: 36 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111808

Other (OTH) AF: 0.00132 AC: 80 AN: 60392

GnomAD4 genome AF: 0.00693 AC: 1056 AN: 152324 Hom.: 10 Cov.: 32 AF XY: 0.00615 AC XY: 458 AN XY: 74490

African (AFR) AF: 0.0243 AC: 1009 AN: 41582

American (AMR) AF: 0.00196 AC: 30 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00234 Hom.: 13

Bravo AF: 0.00797

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00203 AC: 247

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Joubert syndrome 15 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.4
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.28
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.95	P
Vest4		0.84
MVP		0.79
MPC		0.23
ClinPred		0.020	T
GERP RS		6.0
Varity_R		0.57
gMVP		0.79
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs113941736; hg19: chr7-130040587;