rs199993353

Variant names:

• chr11-74028375-T-C
• rs199993353
• NM_001286577.2:c.6833A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_001286577.2(C2CD3):​c.6833A>G​(p.Asn2278Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000284 in 1,535,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: C2CD3 NM_001286577.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.54
• Publications: 1 publications found

Genes affected

C2CD3 (HGNC:24564): (C2 domain containing 3 centriole elongation regulator) This gene encodes a protein that functions as a regulator of centriole elongation. Studies of the orthologous mouse protein show that it promotes centriolar distal appendage assembly and is also required for the recruitment of other ciliogenic proteins, including intraflagellar transport proteins. Mutations in this gene cause orofaciodigital syndrome XIV (OFD14), a ciliopathy resulting in malformations of the oral cavity, face and digits. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Nov 2014]

C2CD3 Gene-Disease associations (from GenCC):

• orofaciodigital syndrome type 14

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ENSG00000298570 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08335778).
• BP6: Variant 11-74028375-T-C is Benign according to our data. Variant chr11-74028375-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 444263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000275 (381/1383708) while in subpopulation MID AF = 0.00353 (20/5670). AF 95% confidence interval is 0.00234. There are 0 homozygotes in GnomAdExome4. There are 210 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286577.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD3	NM_001286577.2	MANE Select	c.6833A>G	p.Asn2278Ser	missense	Exon 32 of 33	NP_001273506.1	Q4AC94-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD3	ENST00000334126.12	TSL:5 MANE Select	c.6833A>G	p.Asn2278Ser	missense	Exon 32 of 33	ENSP00000334379.7	Q4AC94-5
	C2CD3	ENST00000680231.1		c.6833A>G	p.Asn2278Ser	missense	Exon 32 of 33	ENSP00000505413.1	A0A7P0Z475
	C2CD3	ENST00000681143.1		c.6428A>G	p.Asn2143Ser	missense	Exon 29 of 30	ENSP00000505970.1	A0A7P0Z4H1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000917

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: 0.000426

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000417 AC: 57 AN: 136664 AF XY: 0.000458

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.000614

Gnomad ASJ exome AF: 0.000242

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000655

Gnomad OTH exome AF: 0.000718

GnomAD4 exome AF: 0.000275 AC: 381 AN: 1383708 Hom.: 0 Cov.: 30 AF XY: 0.000308 AC XY: 210 AN XY: 682800

African (AFR) AF: 0.000127 AC: 4 AN: 31590

American (AMR) AF: 0.000644 AC: 23 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.0000795 AC: 2 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.000139 AC: 11 AN: 79224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33912

Middle Eastern (MID) AF: 0.00353 AC: 20 AN: 5670

European-Non Finnish (NFE) AF: 0.000272 AC: 293 AN: 1078820

Other (OTH) AF: 0.000484 AC: 28 AN: 57900

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74454

African (AFR) AF: 0.0000722 AC: 3 AN: 41546

American (AMR) AF: 0.000915 AC: 14 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000408

ExAC AF: 0.000102 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.5
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.056
Sift	Uncertain	0.012	D
Sift4G	Benign	0.081	T
Vest4		0.62
MVP		0.38
ClinPred		0.20	T
GERP RS		5.6
Varity_R		0.14
gMVP		0.55
Mutation Taster		=87/13	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs199993353; hg19: chr11-73739420;