2-201491839-T-A

Variant names:

• chr2-201491839-T-A
• rs1039755845
• NM_001168221.2:c.4502A>T

Variant summary

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

The NM_001168221.2(C2CD6):​c.4502A>T​(p.Asp1501Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,384,700 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: C2CD6 NM_001168221.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2CD6	NM_001168221.2	c.4502A>T	p.Asp1501Val	missense_variant	Exon 15 of 16	ENST00000439140.6	NP_001161693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2CD6	ENST00000439140.6	c.4502A>T	p.Asp1501Val	missense_variant	Exon 15 of 16	1	NM_001168221.2	ENSP00000409937.1
C2CD6	ENST00000286195.7	c.1582-3937A>T		intron_variant	Intron 14 of 14	1		ENSP00000286195.3
C2CD6	ENST00000439802.5	c.*50-3937A>T		intron_variant	Intron 12 of 12	2		ENSP00000400672.1
C2CD6	ENST00000482942.1	n.101-3937A>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000141 AC: 2 AN: 141802 Hom.: 0 AF XY: 0.0000132 AC XY: 1 AN XY: 75888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000814

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1384700 Hom.: 0 Cov.: 33 AF XY: 0.00000293 AC XY: 2 AN XY: 683282

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000841

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4502A>T (p.D1501V) 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 4502, causing the aspartic acid (D) at amino acid position 1501 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	-0.23	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.64	T
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.030	D
Vest4		0.45
MutPred		0.45		Gain of sheet (P = 0.0061);
MVP		0.64
MPC		0.72
ClinPred		0.98	D
GERP RS		5.2
gMVP		0.10

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: rs1039755845; hg19: chr2-202356562;