19-13923430-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_017721.5(CC2D1A):c.1739C>T(p.Thr580Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,614,038 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 24 hom. )

Consequence

CC2D1A
NM_017721.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:6

Conservation

PhyloP100: 1.50

Publications

8 publications found

Variant links:

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

CC2D1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077696443).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00463 (706/152336) while in subpopulation NFE AF = 0.0066 (449/68026). AF 95% confidence interval is 0.0061. There are 4 homozygotes in GnomAd4. There are 370 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 4 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.1739C>T	p.Thr580Ile	missense	Exon 15 of 29	NP_060191.3
	CC2D1A	NM_001411138.1		c.1739C>T	p.Thr580Ile	missense	Exon 15 of 29	NP_001398067.1	Q6P1N0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CC2D1A	ENST00000318003.11	TSL:1 MANE Select	c.1739C>T	p.Thr580Ile	missense	Exon 15 of 29	ENSP00000313601.6	Q6P1N0-1
CC2D1A	ENST00000589606.5	TSL:1	c.1739C>T	p.Thr580Ile	missense	Exon 15 of 29	ENSP00000467526.1	Q6P1N0-2
CC2D1A	ENST00000586955.5	TSL:1	n.*6C>T		non_coding_transcript_exon	Exon 10 of 24	ENSP00000465376.1	K7EJY5

Frequencies

GnomAD3 genomes

AF:

0.00463

AC:

705

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00866

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00660

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00508

AC:

1264

AN:

249050

AF XY:

0.00537

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00510

Gnomad ASJ exome

AF:

0.00378

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00961

Gnomad NFE exome

AF:

0.00639

Gnomad OTH exome

AF:

0.00596

GnomAD4 exome

AF:

0.00545

AC:

7965

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00543

AC XY:

3951

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

33480

American (AMR)

AF:

0.00519

AC:

232

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00333

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00205

AC:

177

AN:

86256

European-Finnish (FIN)

AF:

0.00905

AC:

482

AN:

53252

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00595

AC:

6612

AN:

1111996

Other (OTH)

AF:

0.00507

AC:

306

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

442

883

1325

1766

2208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00463

AC:

706

AN:

152336

Hom.:

Cov.:

AF XY:

0.00497

AC XY:

370

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41598

American (AMR)

AF:

0.00464

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00145

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00866

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00660

AC:

449

AN:

68026

Other (OTH)

AF:

0.00616

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00575

Hom.:

Bravo

AF:

0.00437

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00123

AC:

ESP6500EA

AF:

0.00696

AC:

ExAC

AF:

0.00470

AC:

568

EpiCase

AF:

0.00616

EpiControl

AF:

0.00729

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

CC2D1A-related disorder (1)

Inborn genetic diseases (1)

Intellectual disability, autosomal recessive 3 (1)

not specified (1)

Smith-Magenis Syndrome-like (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.090

Eigen

Benign

-0.035

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0078

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

1.5

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.3

REVEL

Benign

0.025

Sift

Benign

0.27

Sift4G

Benign

0.33

Polyphen

0.24

Vest4

0.51

MVP

0.37

MPC

0.29

ClinPred

0.011

GERP RS

5.2

PromoterAI

0.035

Neutral

(source)

Varity_R

0.060

gMVP

0.23

Mutation Taster

=98/2

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over