19-13906455-A-AAGGACCCCC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4BS1_SupportingBS2

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
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_017721.5.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 1109 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CC2D1ANM_017721.5 linkc.15_23dupAGGACCCCC p.Pro8_Gly9insGlyProPro disruptive_inframe_insertion 1/29 ENST00000318003.11 NP_060191.3 Q6P1N0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CC2D1AENST00000318003.11 linkc.15_23dupAGGACCCCC p.Pro8_Gly9insGlyProPro disruptive_inframe_insertion 1/291 NM_017721.5 ENSP00000313601.6 Q6P1N0-1

Frequencies

GnomAD3 genomes
AF:
0.00105
AC:
160
AN:
152014
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.000495
AC:
56
AN:
113052
Hom.:
0
AF XY:
0.000494
AC XY:
31
AN XY:
62816
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 SAS 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.:
3
Cov.:
30
AF XY:
0.00165
AC XY:
1109
AN XY:
673390
show subpopulations
Gnomad4 AFR exome
AF:
0.000241
Gnomad4 AMR exome
AF:
0.000549
Gnomad4 ASJ exome
AF:
0.0000411
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000432
Gnomad4 NFE exome
AF:
0.00205
Gnomad4 OTH exome
AF:
0.00122
GnomAD4 genome
AF:
0.00105
AC:
160
AN:
152130
Hom.:
0
Cov.:
32
AF XY:
0.000995
AC XY:
74
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00104
Gnomad4 NFE
AF:
0.00188
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000237
Hom.:
0

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
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 31, 2016- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Intellectual disability, autosomal recessive 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsNov 29, 2018This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 20, 2022This 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

Splicing

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.

Other links and lift over

dbSNP: rs755038966; hg19: chr19-14017268; API