19-13906455-A-AAGGACCCCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4BP6BS1BS2

The NM_017721.5(CC2D1A):c.15_23dupAGGACCCCC(p.Pro8_Gly9insGlyProPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,517,520 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P8P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 3 hom. )

Consequence

CC2D1A
NM_017721.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.287

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 links:

BRME1 (HGNC:28153): (break repair meiotic recombinase recruitment factor 1) Predicted to be involved in meiosis I and spermatogenesis. Predicted to be located in chromosome. [provided by Alliance of Genome Resources, Apr 2022]

BRME1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_017721.5.

BP6

Variant 19-13906455-A-AAGGACCCCC is Benign according to our data. Variant chr19-13906455-A-AAGGACCCCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434611.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00169 (2303/1365390) while in subpopulation NFE AF = 0.00205 (2190/1066870). AF 95% confidence interval is 0.00198. There are 3 homozygotes in GnomAdExome4. There are 1109 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D1A	NM_017721.5 link	c.15_23dupAGGACCCCC	p.Pro8_Gly9insGlyProPro	disruptive_inframe_insertion	Exon 1 of 29	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.15_23dupAGGACCCCC	p.Pro8_Gly9insGlyProPro	disruptive_inframe_insertion	Exon 1 of 29	1	NM_017721.5	ENSP00000313601.6		Q6P1N0-1

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000495

AC:

AN:

113052

AF XY:

0.000494

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000339

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000108

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.000627

GnomAD4 exome

AF:

0.00169

AC:

2303

AN:

1365390

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1109

AN XY:

673390

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

29068

American (AMR)

AF:

0.000549

AC:

AN:

32770

Ashkenazi Jewish (ASJ)

AF:

0.0000411

AC:

AN:

24310

East Asian (EAS)

AF:

0.00

AC:

AN:

31962

South Asian (SAS)

AF:

0.00

AC:

AN:

76774

European-Finnish (FIN)

AF:

0.000432

AC:

AN:

41660

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5266

European-Non Finnish (NFE)

AF:

0.00205

AC:

2190

AN:

1066870

Other (OTH)

AF:

0.00122

AC:

AN:

56710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

115

230

346

461

576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

152130

Hom.:

Cov.:

AF XY:

0.000995

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41520

American (AMR)

AF:

0.000588

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00188

AC:

128

AN:

67936

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000237

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 31, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Intellectual disability, autosomal recessive 3

Uncertain:1

Nov 29, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Inborn genetic diseases

Benign:1

May 20, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.29

Mutation Taster

=81/19

polymorphism

(source)

Splicing

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

Publications

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19-13906455-A-AAGGACCCCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over