chr1-944729-C-G

Variant names:

• chr1-944729-C-G
• rs550652895
• NM_015658.4:c.2215G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015658.4(NOC2L):​c.2215G>C​(p.Glu739Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NOC2L NM_015658.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.12

Genes affected

NOC2L (HGNC:24517): (NOC2 like nucleolar associated transcriptional repressor) Histone modification by histone acetyltransferases (HAT) and histone deacetylases (HDAC) can control major aspects of transcriptional regulation. NOC2L represents a novel HDAC-independent inhibitor of histone acetyltransferase (INHAT) (Hublitz et al., 2005 [PubMed 16322561]).[supplied by OMIM, Mar 2008]

SAMD11 (HGNC:28706): (sterile alpha motif domain containing 11) Predicted to enable several functions, including histone binding activity; protein domain specific binding activity; and protein self-association. Predicted to be involved in negative regulation of transcription, DNA-templated. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05401483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOC2L	NM_015658.4	c.2215G>C	p.Glu739Gln	missense_variant	Exon 19 of 19	ENST00000327044.7	NP_056473.3
SAMD11	NM_001385641.1	c.*576C>G		downstream_gene_variant		ENST00000616016.5	NP_001372570.1
SAMD11	NM_001385640.1	c.*576C>G		downstream_gene_variant			NP_001372569.1
SAMD11	NM_152486.4	c.*576C>G		downstream_gene_variant			NP_689699.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOC2L	ENST00000327044.7	c.2215G>C	p.Glu739Gln	missense_variant	Exon 19 of 19	1	NM_015658.4	ENSP00000317992.6
SAMD11	ENST00000616016.5	c.*576C>G		downstream_gene_variant		5	NM_001385641.1	ENSP00000478421.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000428 AC: 1 AN: 233802 Hom.: 0 AF XY: 0.00000774 AC XY: 1 AN XY: 129124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000924

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448410 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 720998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2215G>C (p.E739Q) alteration is located in exon 19 (coding exon 19) of the NOC2L gene. This alteration results from a G to C substitution at nucleotide position 2215, causing the glutamic acid (E) at amino acid position 739 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.8
DANN	Benign	0.77
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.051
Sift	Benign	0.044	D
Sift4G	Benign	0.48	T
Polyphen		0.028	B
Vest4		0.12
MutPred		0.076		Gain of helix (P = 0.2059);
MVP		0.31
ClinPred		0.075	T
GERP RS		2.0
Varity_R		0.067
gMVP		0.031

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

LitVar

Other links and lift over

dbSNP: rs550652895; hg19: chr1-880109;