Genetic Variant NM_017721.5:c.748+1G>T (chr19-13913639-G-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017721.5(CC2D1A):c.748+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000691 in 1,446,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CC2D1A
NM_017721.5 splice_donor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 3.71

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.5, offset of 4, new splice context is: tagGTgatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-13913639-G-T is Pathogenic according to our data. Variant chr19-13913639-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 228325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13913639-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D1A	NM_017721.5 link	c.748+1G>T		splice_donor_variant, intron_variant	Intron 6 of 28	ENST00000318003.11	NP_060191.3	Q6P1N0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D1A	ENST00000318003.11 link	c.748+1G>T		splice_donor_variant, intron_variant	Intron 6 of 28	1	NM_017721.5	ENSP00000313601.6		Q6P1N0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446844

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718292

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 3

Pathogenic:3

Nov 26, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Apr 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease and demonstrated complete skipping of exon 6, leading to a premature stop codon (Manzini et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25066123, 28454995, 31130284, 32552793) -

Intellectual disability

Pathogenic:1

Jul 15, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.748+1G>T variant in CC2D1A has been reported in 2 Saudi Arabian families w ith spectrum of neurodevelopmental phenotypes, including nonsyndromic intellectu al disability, language impairment, autism spectrum disorder and seizures (Manzi ni 2014). The variant segregated with disease in a reccessive manner in a total of 11 individuals from both families and was absent from large population studie s. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and was shown to cause skipping of exon 6, resulting in complete loss of CC2D1A protein expression (Manzini 2014). In summary, this variant meets our criteria to be classified as pathogenic for nonsyndromic intellectual disability with or without seizures in an autosomal recessive manner (http://www.partners. org/personalizedmedicine/LMM) based upon segregation studies, absence from contr ols and functional studies. -

Autism

Pathogenic:1

Centre for Addiction & Mental Health, Centre for Addiction & Mental Health

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Putative loss-of-function variant, biallelic, in known disease gene; effect of canonical splice donor variant not yet validated -

Premature ovarian failure 19

Uncertain:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.86

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.91

GERP RS

3.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.98

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over