NM_017721.5:c.513+6_513+12delTGGGCAG

Variant names:

• chr19-13913305-AAGTGGGC-A
• rs541952457
• NM_017721.5:c.513+6_513+12delTGGGCAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_017721.5(CC2D1A):​c.513+6_513+12delTGGGCAG variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0027 in 1,611,536 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: CC2D1A NM_017721.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.44

Genes affected

CC2D1A (HGNC:30237): (coiled-coil and C2 domain containing 1A) This gene encodes a transcriptional repressor that binds to a conserved 14-bp 5'-repressor element and regulates expression of the 5-hydroxytryptamine (serotonin) receptor 1A gene in neuronal cells. The DNA binding and transcriptional repressor activities of the protein are inhibited by calcium. A mutation in this gene results in a nonsyndromic form of cognitive disability (MRT3). [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 19-13913305-AAGTGGGC-A is Benign according to our data. Variant chr19-13913305-AAGTGGGC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128612.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00186 (283/152336) while in subpopulation AMR AF= 0.00307 (47/15300). AF 95% confidence interval is 0.00237. There are 0 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D1A	NM_017721.5	c.513+6_513+12delTGGGCAG		splice_region_variant, intron_variant	Intron 5 of 28	ENST00000318003.11	NP_060191.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D1A	ENST00000318003.11	c.513+4_513+10delAGTGGGC		splice_region_variant, intron_variant	Intron 5 of 28	1	NM_017721.5	ENSP00000313601.6

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00160 AC: 394 AN: 245750 Hom.: 1 AF XY: 0.00165 AC XY: 220 AN XY: 133492

Gnomad AFR exome AF: 0.000650

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00502

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000890

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.00279 AC: 4066 AN: 1459200 Hom.: 5 AF XY: 0.00266 AC XY: 1933 AN XY: 725694

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00667

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00321

Gnomad4 OTH exome AF: 0.00317

GnomAD4 genome AF: 0.00186 AC: 283 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74494

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00251

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00364 Hom.: 0

Bravo AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CC2D1A: BP4 -

Jul 17, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

May 20, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs541952457; hg19: chr19-14024118;