rs16892134

Variant names:

• chr4-15538112-G-A
• rs16892134
• NM_001378615.1:c.1978G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-15538112-G-A
• chr4-15538112-G-C
• chr4-15538112-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378615.1(CC2D2A):​c.1978G>A​(p.Val660Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,595,412 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V660L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (15 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.309
• Publications: 8 publications found

Genes affected

CC2D2A (HGNC:29253): (coiled-coil and C2 domain containing 2A) This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation. Mutations in this gene cause Meckel syndrome type 6, as well as Joubert syndrome type 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

CC2D2A Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 93

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003638178).
• BP6: Variant 4-15538112-G-A is Benign according to our data. Variant chr4-15538112-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210608.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.006 (914/152220) while in subpopulation AFR AF = 0.0208 (862/41536). AF 95% confidence interval is 0.0196. There are 7 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378615.1. 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
	CC2D2A	NM_001378615.1	MANE Select	c.1978G>A	p.Val660Ile	missense	Exon 16 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.1978G>A	p.Val660Ile	missense	Exon 17 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.1831G>A	p.Val611Ile	missense	Exon 14 of 35	NP_001365546.1	H0Y941

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.1978G>A	p.Val660Ile	missense	Exon 16 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.1978G>A	p.Val660Ile	missense	Exon 17 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000513811.5	TSL:1	n.2158G>A		non_coding_transcript_exon	Exon 16 of 18

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 905 AN: 152102 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00139 AC: 308 AN: 221472 AF XY: 0.00104

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.000830

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000803

Gnomad OTH exome AF: 0.00127

GnomAD4 exome AF: 0.000714 AC: 1030 AN: 1443192 Hom.: 15 Cov.: 33 AF XY: 0.000580 AC XY: 415 AN XY: 715450

African (AFR) AF: 0.0252 AC: 837 AN: 33152

American (AMR) AF: 0.00125 AC: 53 AN: 42340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25516

East Asian (EAS) AF: 0.00 AC: 0 AN: 39026

South Asian (SAS) AF: 0.0000481 AC: 4 AN: 83162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52436

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5710

European-Non Finnish (NFE) AF: 0.0000535 AC: 59 AN: 1102152

Other (OTH) AF: 0.00119 AC: 71 AN: 59698

GnomAD4 genome AF: 0.00600 AC: 914 AN: 152220 Hom.: 7 Cov.: 32 AF XY: 0.00579 AC XY: 431 AN XY: 74414

African (AFR) AF: 0.0208 AC: 862 AN: 41536

American (AMR) AF: 0.00183 AC: 28 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68008

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00216 Hom.: 3

Bravo AF: 0.00737

ESP6500AA AF: 0.0212 AC: 93

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00156 AC: 189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Joubert syndrome 9 (1)
-	1	-	Meckel syndrome, type 6 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.37
DANN	Benign	0.30
DEOGEN2	Benign	0.053	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N
PhyloP100		0.31
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.019
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.041	B
Vest4		0.044
MVP		0.14
MPC		0.038
ClinPred		0.00064	T
GERP RS		1.5
Varity_R		0.018
gMVP		0.11
Mutation Taster		=100/0	polymorphism

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: rs16892134; hg19: chr4-15539735;