2-201492136-T-A

Position:

• chr2-201492136-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001168221.2(C2CD6):​c.4205A>T​(p.Asp1402Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C2CD6 NM_001168221.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.176

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]

C2CD6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13612917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C2CD6	NM_001168221.2	c.4205A>T	p.Asp1402Val	missense_variant	15/16	ENST00000439140.6	NP_001161693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C2CD6	ENST00000439140.6	c.4205A>T	p.Asp1402Val	missense_variant	15/16	1	NM_001168221.2	ENSP00000409937.1
C2CD6	ENST00000286195.7	c.1581+3759A>T		intron_variant		1		ENSP00000286195.3
C2CD6	ENST00000439802.5	c.*49+3759A>T		intron_variant		2		ENSP00000400672.1
C2CD6	ENST00000482942.1	n.101-4234A>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2024

The c.4205A>T (p.D1402V) alteration is located in exon 15 (coding exon 15) of the ALS2CR11 gene. This alteration results from a A to T substitution at nucleotide position 4205, causing the aspartic acid (D) at amino acid position 1402 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Uncertain	0.98
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.020
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.040	D
Vest4		0.26
MutPred		0.23		Loss of solvent accessibility (P = 0.0169);
MVP		0.36
MPC		0.53
ClinPred		0.61	D
GERP RS		1.2
gMVP		0.098

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-202356859;