rs12623687

Variant names:

• chr2-181549631-T-C
• rs12623687
• NM_201548.5:c.895+3A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-181549631-T-C
• chr2-181549631-T-A
• chr2-181549631-T-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_201548.5(CERKL):​c.895+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,593,064 control chromosomes in the GnomAD database, including 13,141 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1568 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11573 hom.)
• Consequence: CERKL NM_201548.5 splice_region, intron
• Scores: Splicing: ADA: 0.9723
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.50
• Publications: 10 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 2-181549631-T-C is Benign according to our data. Variant chr2-181549631-T-C is described in ClinVar as Benign. ClinVar VariationId is 257151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 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.895+3A>G		splice_region intron	N/A	NP_963842.1	Q49MI3-2
	CERKL	NM_001030311.3		c.973+3A>G		splice_region intron	N/A	NP_001025482.1	Q49MI3-1
	CERKL	NM_001160277.2		c.841+3A>G		splice_region 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.895+3A>G		splice_region intron	N/A	ENSP00000386725.3	Q49MI3-2
	CERKL	ENST00000339098.9	TSL:1	c.973+3A>G		splice_region intron	N/A	ENSP00000341159.5	Q49MI3-1
	CERKL	ENST00000374970.6	TSL:1	c.688+3A>G		splice_region intron	N/A	ENSP00000364109.2	Q49MI3-3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20928 AN: 152056 Hom.: 1566 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.138 AC: 34509 AN: 250700 AF XY: 0.129

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.211

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.120 AC: 172495 AN: 1440890 Hom.: 11573 Cov.: 27 AF XY: 0.117 AC XY: 83874 AN XY: 718166

African (AFR) AF: 0.145 AC: 4797 AN: 32984

American (AMR) AF: 0.207 AC: 9219 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.0626 AC: 1627 AN: 25970

East Asian (EAS) AF: 0.222 AC: 8753 AN: 39386

South Asian (SAS) AF: 0.0531 AC: 4560 AN: 85932

European-Finnish (FIN) AF: 0.211 AC: 11247 AN: 53378

Middle Eastern (MID) AF: 0.0577 AC: 329 AN: 5706

European-Non Finnish (NFE) AF: 0.114 AC: 124774 AN: 1093252

Other (OTH) AF: 0.120 AC: 7189 AN: 59664

GnomAD4 genome AF: 0.138 AC: 20954 AN: 152174 Hom.: 1568 Cov.: 32 AF XY: 0.143 AC XY: 10606 AN XY: 74398

African (AFR) AF: 0.150 AC: 6234 AN: 41524

American (AMR) AF: 0.173 AC: 2650 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 233 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1128 AN: 5176

South Asian (SAS) AF: 0.0603 AC: 291 AN: 4826

European-Finnish (FIN) AF: 0.200 AC: 2115 AN: 10584

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8011 AN: 68000

Other (OTH) AF: 0.111 AC: 234 AN: 2112

Alfa AF: 0.123 Hom.: 736

Bravo AF: 0.137

Asia WGS AF: 0.169 AC: 586 AN: 3474

EpiCase AF: 0.107

EpiControl AF: 0.101

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	Retinitis pigmentosa 26 (2)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		3.5
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.60
SpliceAI score (max)		0.090		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: rs12623687; hg19: chr2-182414358; COSMIC: COSV59212725;