19-13906455-A-AAGGACCCCC

Variant names:

• chr19-13906455-A-AAGGACCCCC
• rs755038966
• NM_017721.5:c.15_23dupAGGACCCCC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.287

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]

ACMG classification

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 rank	MANE	Protein	UniProt
CC2D1A	NM_017721.5	c.15_23dupAGGACCCCC	p.Pro8_Gly9insGlyProPro	disruptive_inframe_insertion	Exon 1 of 29	ENST00000318003.11	NP_060191.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D1A	ENST00000318003.11	c.15_23dupAGGACCCCC	p.Pro8_Gly9insGlyProPro	disruptive_inframe_insertion	Exon 1 of 29	1	NM_017721.5	ENSP00000313601.6

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152014 Hom.: 0 Cov.: 32

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

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

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

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:3 Benign:1

Revision: criteria provided, conflicting classifications

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs755038966; hg19: chr19-14017268;