rs587780296

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

CC2D1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal recessive 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128612.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017721.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D1A	NM_017721.5	MANE Select	c.513+6_513+12delTGGGCAG		splice_region intron	N/A	NP_060191.3
	CC2D1A	NM_001411138.1		c.513+6_513+12delTGGGCAG		splice_region intron	N/A	NP_001398067.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D1A	ENST00000318003.11	TSL:1 MANE Select	c.513+4_513+10delAGTGGGC		splice_region intron	N/A	ENSP00000313601.6
	CC2D1A	ENST00000589606.5	TSL:1	c.513+4_513+10delAGTGGGC		splice_region intron	N/A	ENSP00000467526.1
	CC2D1A	ENST00000586955.5	TSL:1	n.48+4_48+10delAGTGGGC		splice_region intron	N/A	ENSP00000465376.1

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

GnomAD2 exomes AF: 0.00160 AC: 394 AN: 245750 AF XY: 0.00165

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 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

African (AFR) AF: 0.000419 AC: 14 AN: 33440

American (AMR) AF: 0.00139 AC: 62 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00667 AC: 173 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 85860

European-Finnish (FIN) AF: 0.00103 AC: 55 AN: 53184

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.00321 AC: 3569 AN: 1110574

Other (OTH) AF: 0.00317 AC: 191 AN: 60290

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

African (AFR) AF: 0.000577 AC: 24 AN: 41590

American (AMR) AF: 0.00307 AC: 47 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00251 AC: 171 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00364 Hom.: 0

Bravo AF: 0.00207

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=91/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs541952457; hg19: chr19-14024118;