2-43675975-C-G

Position:

• chr2-43675975-C-G

Variant summary

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

The NM_001101330.3(C1GALT1C1L):​c.348G>C​(p.Arg116Ser) 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. 9/12 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: C1GALT1C1L NM_001101330.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

Genes affected

C1GALT1C1L (HGNC:51617): (C1GALT1 specific chaperone 1 like) Predicted to enable glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase activity. Predicted to be involved in O-glycan processing, core 1. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHH2 (HGNC:30506): (pleckstrin homology, MyTH4 and FERM domain containing H2) Predicted to enable actin binding activity. Predicted to be involved in negative regulation of actin filament depolymerization. Located in several cellular components, including cytosol; lamellipodium; and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

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=0.14093643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1GALT1C1L	NM_001101330.3	c.348G>C	p.Arg116Ser	missense_variant	1/1	ENST00000475092.4
PLEKHH2	NM_172069.4	c.124-2888C>G		intron_variant		ENST00000282406.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1GALT1C1L	ENST00000475092.4	c.348G>C	p.Arg116Ser	missense_variant	1/1		NM_001101330.3	P1
PLEKHH2	ENST00000282406.9	c.124-2888C>G		intron_variant		1	NM_172069.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249386 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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 Cov.: 60

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

May 31, 2022

The c.348G>C (p.R116S) alteration is located in exon 1 (coding exon 1) of the C1GALT1C1L gene. This alteration results from a G to C substitution at nucleotide position 348, causing the arginine (R) at amino acid position 116 to be replaced by a serine (S). 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
AlphaMissense	Benign	0.17
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.0019	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.14	T
MutationTaster	Benign	0.73	N
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.71	T
Vest4		0.14
GERP RS		-1.4
Varity_R		0.14
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs779846287; hg19: chr2-43903114;