2-201491514-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001168221.2(C2CD6):c.4827G>T(p.Lys1609Asn) 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: 0.391

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, C2CD6
• BP4: Computational evidence support a benign effect (MetaRNN=0.14915323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C2CD6	NM_001168221.2	c.4827G>T	p.Lys1609Asn	missense_variant	15/16	ENST00000439140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C2CD6	ENST00000439140.6	c.4827G>T	p.Lys1609Asn	missense_variant	15/16	1	NM_001168221.2	A2
C2CD6	ENST00000286195.7	c.1582-3612G>T		intron_variant		1		P2
C2CD6	ENST00000439802.5	c.*50-3612G>T		intron_variant		2
C2CD6	ENST00000482942.1	n.101-3612G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Dec 17, 2023

The c.4827G>T (p.K1609N) alteration is located in exon 15 (coding exon 15) of the ALS2CR11 gene. This alteration results from a G to T substitution at nucleotide position 4827, causing the lysine (K) at amino acid position 1609 to be replaced by an asparagine (N). 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	-0.30	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.064
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.034	D
Vest4		0.32
MutPred		0.36		Loss of methylation at K1609 (P = 0.0033);
MVP		0.092
MPC		0.65
ClinPred		0.61	D
GERP RS		-2.4
gMVP		0.12

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: chr2-202356237;