19-13912529-C-T

Variant names:

• chr19-13912529-C-T
• rs192358667
• NM_017721.5:c.314C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_017721.5(CC2D1A):​c.314C>T​(p.Ala105Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,614,122 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A105A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: CC2D1A NM_017721.5 missense, splice_region
• Scores: Splicing: ADA: 0.9254
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.07
• Publications: 2 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0143601).
• BP6: Variant 19-13912529-C-T is Benign according to our data. Variant chr19-13912529-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434594.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00159 (242/152254) while in subpopulation AFR AF = 0.00515 (214/41536). AF 95% confidence interval is 0.00459. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D1A	NM_017721.5	MANE Select	c.314C>T	p.Ala105Val	missense splice_region	Exon 4 of 29	NP_060191.3
	CC2D1A	NM_001411138.1		c.314C>T	p.Ala105Val	missense splice_region	Exon 4 of 29	NP_001398067.1	Q6P1N0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D1A	ENST00000318003.11	TSL:1 MANE Select	c.314C>T	p.Ala105Val	missense splice_region	Exon 4 of 29	ENSP00000313601.6	Q6P1N0-1
	CC2D1A	ENST00000589606.5	TSL:1	c.314C>T	p.Ala105Val	missense splice_region	Exon 4 of 29	ENSP00000467526.1	Q6P1N0-2
	CC2D1A	ENST00000870940.1		c.350C>T	p.Ala117Val	missense	Exon 4 of 29	ENSP00000540999.1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000337 AC: 84 AN: 249342 AF XY: 0.000266

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461868 Hom.: 1 Cov.: 31 AF XY: 0.000146 AC XY: 106 AN XY: 727232

African (AFR) AF: 0.00579 AC: 194 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

Other (OTH) AF: 0.000480 AC: 29 AN: 60396

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74444

African (AFR) AF: 0.00515 AC: 214 AN: 41536

American (AMR) AF: 0.00144 AC: 22 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000528 Hom.: 1

Bravo AF: 0.00189

ESP6500AA AF: 0.00620 AC: 25

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000447 AC: 54

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.12
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.47
MVP		0.68
MPC		0.81
ClinPred		0.085	T
GERP RS		4.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.36
gMVP		0.32
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.79
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: rs192358667; hg19: chr19-14023342;