2-201487740-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001168221.2(C2CD6):c.5335C>T(p.Arg1779Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 1,614,012 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: C2CD6 NM_001168221.2 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.557

Genes affected

C2CD6 (HGNC:14438): (C2 calcium dependent domain containing 6) An autosomal recessive form of juvenile amyotrophic lateral sclerosis was originally mapped to a region of chromosome 2 that includes this gene. The encoded protein contains a calcium-dependent membrane targeting C2 domain. This domain is often found in proteins that are involved in membrane trafficking and signal transduction. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001168221.2 Downstream stopcodon found after 96 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C2CD6	NM_001168221.2	c.5335C>T	p.Arg1779Ter	stop_gained	16/16	ENST00000439140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C2CD6	ENST00000439140.6	c.5335C>T	p.Arg1779Ter	stop_gained	16/16	1	NM_001168221.2	A2
C2CD6	ENST00000286195.7	c.1744C>T	p.Arg582Ter	stop_gained	15/15	1		P2
C2CD6	ENST00000439802.5	c.*212C>T		3_prime_UTR_variant	13/13	2

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.000720 AC: 181 AN: 251452 Hom.: 0 AF XY: 0.000655 AC XY: 89 AN XY: 135898

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000505 AC: 738 AN: 1461850 Hom.: 1 Cov.: 31 AF XY: 0.000488 AC XY: 355 AN XY: 727224

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000417

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.000802 AC: 122 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74384

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000763 Hom.: 0

Bravo AF: 0.00103

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000568 AC: 69

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spermatogenic failure 68 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.0057	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	35
Dann	Benign	0.94
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.026	N
MutationTaster	Benign	0.99	D;D;N
Vest4		0.20
GERP RS		0.78

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: rs140775049; hg19: chr2-202352463; COSMIC: COSV53791001; COSMIC: COSV53791001;