chr1-1398672-CTAGAG-C

Variant names:

• chr1-1398672-CTAGAG-C
• rs3831366
• NM_030937.6:c.289-6_289-2delCTCTA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_030937.6(CCNL2):​c.289-6_289-2delCTCTA variant causes a splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 1,613,414 control chromosomes in the GnomAD database, including 2,392 homozygotes. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.058 (333 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2059 hom.)
• Consequence: CCNL2 NM_030937.6 splice_acceptor, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.63
• Publications: 10 publications found

Genes affected

CCNL2 (HGNC:20570): (cyclin L2) The protein encoded by this gene belongs to the cyclin family. Through its interaction with several proteins, such as RNA polymerase II, splicing factors, and cyclin-dependent kinases, this protein functions as a regulator of the pre-mRNA splicing process, as well as in inducing apoptosis by modulating the expression of apoptotic and antiapoptotic proteins. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.047984645 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.1, offset of 0 (no position change), new splice context is: atacggaaactttcttctAGgtg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0843 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030937.6. 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
	CCNL2	NM_030937.6	MANE Select	c.289-6_289-2delCTCTA		splice_acceptor splice_region intron	N/A	NP_112199.2	Q96S94-1
	CCNL2	NM_001350499.2		c.-509-6_-509-2delCTCTA		splice_acceptor splice_region intron	N/A	NP_001337428.1
	CCNL2	NM_001350500.2		c.-398-6_-398-2delCTCTA		splice_acceptor splice_region intron	N/A	NP_001337429.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCNL2	ENST00000400809.8	TSL:1 MANE Select	c.289-6_289-2delCTCTA		splice_acceptor splice_region intron	N/A	ENSP00000383611.3	Q96S94-1
	CCNL2	ENST00000408918.8	TSL:1	c.289-6_289-2delCTCTA		splice_acceptor splice_region intron	N/A	ENSP00000386158.4	Q96S94-5
	CCNL2	ENST00000497013.1	TSL:2	c.-12_-8delCTCTA		5_prime_UTR	Exon 1 of 3	ENSP00000464685.1	J3QSH2

Frequencies

GnomAD3 genomes AF: 0.0583 AC: 8879 AN: 152176 Hom.: 329 Cov.: 32

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0379

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.0910

Gnomad SAS AF: 0.0815

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0536 AC: 13471 AN: 251316 AF XY: 0.0544

Gnomad AFR exome AF: 0.0835

Gnomad AMR exome AF: 0.0231

Gnomad ASJ exome AF: 0.0265

Gnomad EAS exome AF: 0.0838

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0399

Gnomad OTH exome AF: 0.0582

GnomAD4 exome AF: 0.0482 AC: 70418 AN: 1461120 Hom.: 2059 AF XY: 0.0489 AC XY: 35528 AN XY: 726890

African (AFR) AF: 0.0839 AC: 2807 AN: 33460

American (AMR) AF: 0.0253 AC: 1132 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 737 AN: 26130

East Asian (EAS) AF: 0.101 AC: 4029 AN: 39698

South Asian (SAS) AF: 0.0797 AC: 6870 AN: 86248

European-Finnish (FIN) AF: 0.102 AC: 5429 AN: 53266

Middle Eastern (MID) AF: 0.0583 AC: 336 AN: 5764

European-Non Finnish (NFE) AF: 0.0413 AC: 45892 AN: 1111464

Other (OTH) AF: 0.0528 AC: 3186 AN: 60368

GnomAD4 genome AF: 0.0585 AC: 8906 AN: 152294 Hom.: 333 Cov.: 32 AF XY: 0.0609 AC XY: 4535 AN XY: 74470

African (AFR) AF: 0.0829 AC: 3446 AN: 41558

American (AMR) AF: 0.0378 AC: 578 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3470

East Asian (EAS) AF: 0.0910 AC: 472 AN: 5184

South Asian (SAS) AF: 0.0820 AC: 396 AN: 4832

European-Finnish (FIN) AF: 0.102 AC: 1082 AN: 10598

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0389 AC: 2649 AN: 68022

Other (OTH) AF: 0.0586 AC: 124 AN: 2116

Alfa AF: 0.0465 Hom.: 31

Bravo AF: 0.0539

Asia WGS AF: 0.104 AC: 360 AN: 3478

EpiCase AF: 0.0407

EpiControl AF: 0.0383

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=77/23	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3831366; hg19: chr1-1334052; COSMIC: COSV61224690; COSMIC: COSV61224690;