7-130401961-GAA-GA

Variant names:

• chr7-130401961-GA-G
• rs144531086
• NM_018718.3:c.575-14delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_018718.3(CEP41):​c.575-14delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,594,694 control chromosomes in the GnomAD database, including 243 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., cov: 31)
  • Exomes 𝑓: 0.016 (226 hom.)
• Consequence: CEP41 NM_018718.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.18
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 7-130401961-GA-G is Benign according to our data. Variant chr7-130401961-GA-G is described in ClinVar as Benign. ClinVar VariationId is 261055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0128 (1952/152286) while in subpopulation NFE AF = 0.0194 (1319/68024). AF 95% confidence interval is 0.0185. There are 17 homozygotes in GnomAd4. There are 991 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.575-14delT		intron	N/A	NP_061188.1	Q9BYV8-1
	CEP41	NM_001257158.2		c.575-14delT		intron	N/A	NP_001244087.1	Q9BYV8-2
	CEP41	NM_001257159.2		c.527-14delT		intron	N/A	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.575-14delT		intron	N/A	ENSP00000223208.4	Q9BYV8-1
	CEP41	ENST00000343969.10	TSL:1	c.575-14delT		intron	N/A	ENSP00000342738.6	A0A7I2PK71
	CEP41	ENST00000484549.6	TSL:1	n.*747-14delT		intron	N/A	ENSP00000419078.2	C9IZ34

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1954 AN: 152168 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.0132 AC: 3310 AN: 251318 AF XY: 0.0134

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0315

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0156 AC: 22497 AN: 1442408 Hom.: 226 Cov.: 25 AF XY: 0.0157 AC XY: 11293 AN XY: 718582

African (AFR) AF: 0.00194 AC: 64 AN: 33060

American (AMR) AF: 0.00472 AC: 211 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00400 AC: 104 AN: 26000

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39572

South Asian (SAS) AF: 0.00831 AC: 714 AN: 85870

European-Finnish (FIN) AF: 0.0315 AC: 1678 AN: 53310

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5740

European-Non Finnish (NFE) AF: 0.0173 AC: 18958 AN: 1094502

Other (OTH) AF: 0.0126 AC: 751 AN: 59684

GnomAD4 genome AF: 0.0128 AC: 1952 AN: 152286 Hom.: 17 Cov.: 31 AF XY: 0.0133 AC XY: 991 AN XY: 74464

African (AFR) AF: 0.00318 AC: 132 AN: 41566

American (AMR) AF: 0.00595 AC: 91 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4824

European-Finnish (FIN) AF: 0.0327 AC: 347 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0194 AC: 1319 AN: 68024

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0114 Hom.: 4

Bravo AF: 0.00962

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Joubert syndrome 15 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs144531086; hg19: chr7-130041802;