11-74085638-T-C

Variant names:

• chr11-74085638-T-C
• rs1095423
• NM_001286577.2:c.3890A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286577.2(C2CD3):​c.3890A>G​(p.Tyr1297Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,614,100 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (403 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (378 hom.)
• Consequence: C2CD3 NM_001286577.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.46
• Publications: 9 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002023816).
• BP6: Variant 11-74085638-T-C is Benign according to our data. Variant chr11-74085638-T-C is described in ClinVar as Benign. ClinVar VariationId is 1220770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

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.3890A>G	p.Tyr1297Cys	missense	Exon 21 of 33	NP_001273506.1	Q4AC94-5
	C2CD3	NM_015531.6		c.3890A>G	p.Tyr1297Cys	missense	Exon 21 of 31	NP_056346.3	Q4AC94-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD3	ENST00000334126.12	TSL:5 MANE Select	c.3890A>G	p.Tyr1297Cys	missense	Exon 21 of 33	ENSP00000334379.7	Q4AC94-5
	C2CD3	ENST00000414160.7	TSL:1	c.3890A>G	p.Tyr1297Cys	missense	Exon 21 of 31	ENSP00000388750.3	H7BZB4
	C2CD3	ENST00000313663.11	TSL:1	c.3890A>G	p.Tyr1297Cys	missense	Exon 21 of 31	ENSP00000323339.7	Q4AC94-1

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 6115 AN: 152130 Hom.: 401 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0112 AC: 2810 AN: 251066 AF XY: 0.00826

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.00579

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000494

Gnomad OTH exome AF: 0.00768

GnomAD4 exome AF: 0.00449 AC: 6566 AN: 1461852 Hom.: 378 Cov.: 33 AF XY: 0.00391 AC XY: 2843 AN XY: 727236

African (AFR) AF: 0.143 AC: 4791 AN: 33474

American (AMR) AF: 0.00691 AC: 309 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 444 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.000311 AC: 346 AN: 1111984

Other (OTH) AF: 0.0101 AC: 610 AN: 60394

GnomAD4 genome AF: 0.0403 AC: 6132 AN: 152248 Hom.: 403 Cov.: 32 AF XY: 0.0386 AC XY: 2874 AN XY: 74446

African (AFR) AF: 0.139 AC: 5750 AN: 41490

American (AMR) AF: 0.0138 AC: 211 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68030

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0138 Hom.: 412

Bravo AF: 0.0442

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.126 AC: 554

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.0135 AC: 1640

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.31
MPC		0.56
ClinPred		0.030	T
GERP RS		6.0
Varity_R		0.21
gMVP		0.70
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1095423; hg19: chr11-73796683;