NM_001101330.3:c.399C>G

Variant names:

• chr2-43675924-G-C
• rs774712544
• NM_001101330.3:c.399C>G

Variant summary

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

The NM_001101330.3(C1GALT1C1L):​c.399C>G​(p.Asp133Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: C1GALT1C1L NM_001101330.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0710
• Publications: 0 publications found

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

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=0.08080837).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101330.3. 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
	C1GALT1C1L	NM_001101330.3	MANE Select	c.399C>G	p.Asp133Glu	missense	Exon 1 of 1	NP_001094800.1	P0DN25
	PLEKHH2	NM_172069.4	MANE Select	c.124-2939G>C		intron	N/A	NP_742066.2	Q8IVE3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1GALT1C1L	ENST00000475092.4	TSL:6 MANE Select	c.399C>G	p.Asp133Glu	missense	Exon 1 of 1	ENSP00000489061.1	P0DN25
	PLEKHH2	ENST00000282406.9	TSL:1 MANE Select	c.124-2939G>C		intron	N/A	ENSP00000282406.4	Q8IVE3-1
	PLEKHH2	ENST00000405000.6	TSL:1	n.401-2939G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249832 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461746 Hom.: 0 Cov.: 41 AF XY: 0.0000110 AC XY: 8 AN XY: 727162

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111900

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.56
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.081	T
PhyloP100		0.071
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.093	T
Vest4		0.13
GERP RS		2.5
Varity_R		0.079
gMVP		0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs774712544; hg19: chr2-43903063;