2-181604091-A-T

Variant names:

• chr2-181604091-A-T
• rs6433923
• NM_201548.5:c.239-12T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201548.5(CERKL):​c.239-12T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,577,114 control chromosomes in the GnomAD database, including 19,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (7598 hom., cov: 32)
  • Exomes 𝑓: 0.097 (11478 hom.)
• Consequence: CERKL NM_201548.5 intron
• Scores: Splicing: ADA: 0.0001000
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0670
• Publications: 4 publications found

Genes affected

CERKL (HGNC:21699): (ceramide kinase like) This gene was initially identified as a locus (RP26) associated with an autosomal recessive form of retinitis pigmentosa (arRP) disease. This gene encodes a protein with ceramide kinase-like domains, however, the protein does not phosphorylate ceramide and its target substrate is currently unknown. This protein may be a negative regulator of apoptosis in photoreceptor cells. Mutations in this gene cause a form of retinitis pigmentosa characterized by autosomal recessive cone and rod dystrophy (arCRD). Alternative splicing of this gene results in multiple transcript variants encoding different isoforms and non-coding transcripts.[provided by RefSeq, May 2010]

CERKL Gene-Disease associations (from GenCC):

• CERKL-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 26

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-181604091-A-T is Benign according to our data. Variant chr2-181604091-A-T is described in ClinVar as Benign. ClinVar VariationId is 166848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201548.5. 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
	CERKL	NM_201548.5	MANE Select	c.239-12T>A		intron	N/A	NP_963842.1	Q49MI3-2
	CERKL	NM_001030311.3		c.239-12T>A		intron	N/A	NP_001025482.1	Q49MI3-1
	CERKL	NM_001160277.2		c.239-12T>A		intron	N/A	NP_001153749.1	Q49MI3-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERKL	ENST00000410087.8	TSL:1 MANE Select	c.239-12T>A		intron	N/A	ENSP00000386725.3	Q49MI3-2
	CERKL	ENST00000339098.9	TSL:1	c.239-12T>A		intron	N/A	ENSP00000341159.5	Q49MI3-1
	CERKL	ENST00000374970.6	TSL:1	c.239-12T>A		intron	N/A	ENSP00000364109.2	Q49MI3-3

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35085 AN: 151970 Hom.: 7579 Cov.: 32

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.0341

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.0764

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0797

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.138 AC: 33265 AN: 240622 AF XY: 0.129

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.0789

Gnomad EAS exome AF: 0.123

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0810

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.0969 AC: 138119 AN: 1425026 Hom.: 11478 Cov.: 28 AF XY: 0.0969 AC XY: 68870 AN XY: 710698

African (AFR) AF: 0.588 AC: 18361 AN: 31232

American (AMR) AF: 0.193 AC: 8529 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.0762 AC: 1969 AN: 25834

East Asian (EAS) AF: 0.112 AC: 4405 AN: 39162

South Asian (SAS) AF: 0.122 AC: 10362 AN: 85140

European-Finnish (FIN) AF: 0.117 AC: 6136 AN: 52258

Middle Eastern (MID) AF: 0.146 AC: 802 AN: 5508

European-Non Finnish (NFE) AF: 0.0744 AC: 80554 AN: 1082658

Other (OTH) AF: 0.119 AC: 7001 AN: 59016

GnomAD4 genome AF: 0.231 AC: 35150 AN: 152088 Hom.: 7598 Cov.: 32 AF XY: 0.230 AC XY: 17095 AN XY: 74354

African (AFR) AF: 0.573 AC: 23701 AN: 41398

American (AMR) AF: 0.187 AC: 2853 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0764 AC: 265 AN: 3470

East Asian (EAS) AF: 0.119 AC: 615 AN: 5182

South Asian (SAS) AF: 0.115 AC: 556 AN: 4822

European-Finnish (FIN) AF: 0.120 AC: 1273 AN: 10602

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0797 AC: 5422 AN: 68016

Other (OTH) AF: 0.187 AC: 396 AN: 2116

Alfa AF: 0.0658 Hom.: 123

Bravo AF: 0.254

Asia WGS AF: 0.128 AC: 447 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Retinitis pigmentosa 26 (3)
-	-	2	not provided (2)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.3
DANN	Benign	0.40
PhyloP100		-0.067
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.036
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: rs6433923; hg19: chr2-182468818;