2-201491605-A-G

Variant names:

• chr2-201491605-A-G
• NM_001168221.2:c.4736T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001168221.2(CATSPERT):​c.4736T>C​(p.Leu1579Ser) 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 1,384,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: CATSPERT NM_001168221.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.363
• Publications: 0 publications found

Genes affected

CATSPERT (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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09685767).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001168221.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CATSPERT	NM_001168221.2	MANE Select	c.4736T>C	p.Leu1579Ser	missense	Exon 15 of 16	NP_001161693.1	Q53TS8-4
	CATSPERT	NM_152525.6		c.1582-3703T>C		intron	N/A	NP_689738.3
	CATSPERT	NM_001168216.2		c.*50-3703T>C		intron	N/A	NP_001161688.1	Q53TS8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2CD6	ENST00000439140.6	TSL:1 MANE Select	c.4736T>C	p.Leu1579Ser	missense	Exon 15 of 16	ENSP00000409937.1	Q53TS8-4
	C2CD6	ENST00000286195.7	TSL:1	c.1582-3703T>C		intron	N/A	ENSP00000286195.3	Q53TS8-1
	C2CD6	ENST00000957096.1		c.4313T>C	p.Leu1438Ser	missense	Exon 12 of 13	ENSP00000627155.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1384834 Hom.: 0 Cov.: 33 AF XY: 0.00000293 AC XY: 2 AN XY: 683340

African (AFR) AF: 0.00 AC: 0 AN: 31586

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35696

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078844

Other (OTH) AF: 0.00 AC: 0 AN: 57906

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.7
DANN	Uncertain	0.99
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.36
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.034
Sift	Benign	0.14	T
Sift4G	Benign	0.46	T
Vest4		0.20
MutPred		0.43		Loss of stability (P = 0.0104)
MVP		0.12
MPC		0.24
ClinPred		0.091	T
GERP RS		-3.2
gMVP		0.072
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

hg19: chr2-202356328;