rs75601897

Positions:

• chr19-13920915-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017721.5(CC2D1A):​c.1634T>C​(p.Ile545Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,612,160 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (9 hom.)
• Consequence: CC2D1A NM_017721.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.31

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063429177).
• BP6: Variant 19-13920915-T-C is Benign according to our data. Variant chr19-13920915-T-C is described in ClinVar as [Benign]. Clinvar id is 128617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00702 (1070/152368) while in subpopulation AFR AF= 0.0247 (1028/41590). AF 95% confidence interval is 0.0235. There are 7 homozygotes in gnomad4. There are 508 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D1A	NM_017721.5	c.1634T>C	p.Ile545Thr	missense_variant	14/29	ENST00000318003.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D1A	ENST00000318003.11	c.1634T>C	p.Ile545Thr	missense_variant	14/29	1	NM_017721.5	P3

Frequencies

GnomAD3 genomes AF: 0.00703 AC: 1071 AN: 152250 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00170 AC: 415 AN: 243750 Hom.: 4 AF XY: 0.00128 AC XY: 170 AN XY: 132656

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.000825

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000630 AC: 919 AN: 1459792 Hom.: 9 Cov.: 33 AF XY: 0.000552 AC XY: 401 AN XY: 726116

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.000947

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00702 AC: 1070 AN: 152368 Hom.: 7 Cov.: 32 AF XY: 0.00682 AC XY: 508 AN XY: 74512

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00133 Hom.: 2

Bravo AF: 0.00785

ESP6500AA AF: 0.0233 AC: 97

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00212 AC: 256

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 08, 2013

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2016

This alteration is classified as 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0063	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Benign	0.28
Sift	Benign	0.060	T;.
Sift4G	Uncertain	0.037	D;D
Polyphen		0.99	D;P
Vest4		0.88
MVP		0.58
MPC		0.78
ClinPred		0.018	T
GERP RS		5.5
Varity_R		0.27
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs75601897; hg19: chr19-14031728;