chr4-15538112-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001378615.1(CC2D2A):​c.1978G>C​(p.Val660Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,595,412 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. V660I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009012312).
• BP6: Variant 4-15538112-G-C is Benign according to our data. Variant chr4-15538112-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194716.
• BS2: High Homozygotes in GnomAdExome4 at 8 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>C	p.Val660Leu	missense	Exon 16 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.1978G>C	p.Val660Leu	missense	Exon 17 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.1831G>C	p.Val611Leu	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>C	p.Val660Leu	missense	Exon 16 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.1978G>C	p.Val660Leu	missense	Exon 17 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000513811.5	TSL:1	n.2158G>C		non_coding_transcript_exon	Exon 16 of 18

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00196 AC: 435 AN: 221472 AF XY: 0.00200

Gnomad AFR exome AF: 0.000377

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00554

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000208

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00243 AC: 3510 AN: 1443190 Hom.: 8 Cov.: 33 AF XY: 0.00242 AC XY: 1728 AN XY: 715450

African (AFR) AF: 0.000302 AC: 10 AN: 33154

American (AMR) AF: 0.00208 AC: 88 AN: 42340

Ashkenazi Jewish (ASJ) AF: 0.00443 AC: 113 AN: 25516

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

South Asian (SAS) AF: 0.00236 AC: 196 AN: 83162

European-Finnish (FIN) AF: 0.000210 AC: 11 AN: 52436

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5710

European-Non Finnish (NFE) AF: 0.00266 AC: 2935 AN: 1102148

Other (OTH) AF: 0.00250 AC: 149 AN: 59698

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74416

African (AFR) AF: 0.000481 AC: 20 AN: 41538

American (AMR) AF: 0.00288 AC: 44 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

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

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00243 AC: 165 AN: 68008

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

Alfa AF: 0.000163 Hom.: 3

Bravo AF: 0.00180

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ExAC AF: 0.00172 AC: 208

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	3	not specified (3)
-	1	-	Joubert syndrome 9 (1)
-	1	-	Meckel syndrome, type 6 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.4
DANN	Benign	0.32
DEOGEN2	Benign	0.095	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.31
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.068
Sift	Benign	0.32	T
Sift4G	Uncertain	0.015	D
Polyphen		0.31	B
Vest4		0.18
MutPred		0.12		Gain of glycosylation at T661 (P = 0.0271)
MVP		0.26
MPC		0.045
ClinPred		0.0051	T
GERP RS		1.5
Varity_R		0.052
gMVP		0.29
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;