2-201491719-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001168221.2(C2CD6):c.4622A>C(p.Gln1541Pro) 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. 13/18 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: 1.71

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
• PP2: Missense variant where missense usually causes diseases, C2CD6
• BP4: Computational evidence support a benign effect (MetaRNN=0.28926915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C2CD6	NM_001168221.2	c.4622A>C	p.Gln1541Pro	missense_variant	15/16	ENST00000439140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C2CD6	ENST00000439140.6	c.4622A>C	p.Gln1541Pro	missense_variant	15/16	1	NM_001168221.2	A2
C2CD6	ENST00000286195.7	c.1582-3817A>C		intron_variant		1		P2
C2CD6	ENST00000439802.5	c.*50-3817A>C		intron_variant		2
C2CD6	ENST00000482942.1	n.101-3817A>C		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

Jun 03, 2022

The c.4622A>C (p.Q1541P) alteration is located in exon 15 (coding exon 15) of the ALS2CR11 gene. This alteration results from a A to C substitution at nucleotide position 4622, causing the glutamine (Q) at amino acid position 1541 to be replaced by a proline (P). 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	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	18
Dann	Benign	0.92
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.056
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.044	D
Vest4		0.45
MutPred		0.39		Gain of loop (P = 0.0166);
MVP		0.26
MPC		0.63
ClinPred		0.51	D
GERP RS		2.8
gMVP		0.31

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: chr2-202356442;