rs191830054

Variant names:

• chr19-13919829-A-G
• rs191830054
• NM_017721.5:c.1234A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-13919829-A-G
• chr19-13919829-A-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017721.5(CC2D1A):​c.1234A>G​(p.Ile412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,603,876 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I412M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: CC2D1A NM_017721.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 3.18
• Publications: 5 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), G2P, Ambry Genetics
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010265142).
• BP6: Variant 19-13919829-A-G is Benign according to our data. Variant chr19-13919829-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210590.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00242 (368/152252) while in subpopulation AMR AF = 0.0053 (81/15290). AF 95% confidence interval is 0.00437. There are 0 homozygotes in GnomAd4. There are 173 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D1A	NM_017721.5	MANE Select	c.1234A>G	p.Ile412Val	missense	Exon 12 of 29	NP_060191.3
	CC2D1A	NM_001411138.1		c.1234A>G	p.Ile412Val	missense	Exon 12 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.1234A>G	p.Ile412Val	missense	Exon 12 of 29	ENSP00000313601.6	Q6P1N0-1
	CC2D1A	ENST00000589606.5	TSL:1	c.1234A>G	p.Ile412Val	missense	Exon 12 of 29	ENSP00000467526.1	Q6P1N0-2
	CC2D1A	ENST00000586955.5	TSL:1	n.757+627A>G		intron	N/A	ENSP00000465376.1	K7EJY5

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 368 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00238 AC: 590 AN: 248050 AF XY: 0.00237

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.00391

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00415

GnomAD4 exome AF: 0.00281 AC: 4075 AN: 1451624 Hom.: 5 Cov.: 30 AF XY: 0.00275 AC XY: 1978 AN XY: 720566

African (AFR) AF: 0.000844 AC: 28 AN: 33166

American (AMR) AF: 0.00378 AC: 167 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.00412 AC: 107 AN: 26000

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39408

South Asian (SAS) AF: 0.000244 AC: 21 AN: 85926

European-Finnish (FIN) AF: 0.000769 AC: 41 AN: 53316

Middle Eastern (MID) AF: 0.00247 AC: 11 AN: 4454

European-Non Finnish (NFE) AF: 0.00319 AC: 3521 AN: 1105372

Other (OTH) AF: 0.00298 AC: 178 AN: 59752

GnomAD4 genome AF: 0.00242 AC: 368 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74454

African (AFR) AF: 0.00113 AC: 47 AN: 41556

American (AMR) AF: 0.00530 AC: 81 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00298 AC: 203 AN: 68014

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00261 Hom.: 5

Bravo AF: 0.00273

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000803 AC: 3

ESP6500EA AF: 0.00280 AC: 23

ExAC AF: 0.00204 AC: 246

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00405

EpiControl AF: 0.00451

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	2	-	Intellectual disability, autosomal recessive 3 (2)
-	-	1	CC2D1A-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.0039
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.070
Sift	Uncertain	0.018	D
Sift4G	Benign	0.093	T
Polyphen		0.10	B
Vest4		0.15
MVP		0.34
MPC		0.31
ClinPred		0.031	T
GERP RS		4.9
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.11
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs191830054; hg19: chr19-14030642;