Genetic Variant NM_017721.5:c.65G>T (chr19-13909827-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_017721.5(CC2D1A):c.65G>T(p.Gly22Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G22D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CC2D1A
NM_017721.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.85

Publications

0 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), Ambry Genetics, G2P
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CC2D1A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D1A	NM_017721.5 link	c.65G>T	p.Gly22Val	missense_variant	Exon 2 of 29	ENST00000318003.11	NP_060191.3	Q6P1N0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CC2D1A	ENST00000318003.11 link	c.65G>T	p.Gly22Val	missense_variant	Exon 2 of 29	1	NM_017721.5	ENSP00000313601.6	Q6P1N0-1
CC2D1A	ENST00000589606.5 link	c.65G>T	p.Gly22Val	missense_variant	Exon 2 of 29	1		ENSP00000467526.1	Q6P1N0-2
CC2D1A	ENST00000585896.5 link	n.304G>T		non_coding_transcript_exon_variant	Exon 2 of 10	2
CC2D1A	ENST00000680439.1 link	n.223G>T		non_coding_transcript_exon_variant	Exon 2 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1435956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710610

African (AFR)

AF:

0.00

AC:

AN:

32924

American (AMR)

AF:

0.00

AC:

AN:

42686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24850

East Asian (EAS)

AF:

0.00

AC:

AN:

39146

South Asian (SAS)

AF:

0.00

AC:

AN:

83802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094874

Other (OTH)

AF:

0.00

AC:

AN:

59234

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Benign

-0.75

MutationAssessor

Pathogenic

3.1

M;M

PhyloP100

6.8

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.4

D;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.99

D;D

Vest4

0.82

MutPred

0.62

Loss of disorder (P = 0.0405);Loss of disorder (P = 0.0405);

MVP

0.61

MPC

0.91

ClinPred

1.0

GERP RS

5.4

Varity_R

0.88

gMVP

0.94

Mutation Taster

=60/40

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over