chr14-39128333-C-G

Variant names:

• chr14-39128333-C-G
• rs1015471843
• NM_003616.3:c.585C>G

Variant summary

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

The NM_003616.3(GEMIN2):​c.585C>G​(p.Asp195Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,411,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D195G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GEMIN2 NM_003616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0580
• Publications: 0 publications found

Genes affected

GEMIN2 (HGNC:10884): (gem nuclear organelle associated protein 2) This gene encodes one of the proteins found in the SMN complex, which consists of several gemin proteins and the protein known as the survival of motor neuron protein. The SMN complex is localized to a subnuclear compartment called gems (gemini of coiled bodies) and is required for assembly of spliceosomal snRNPs and for pre-mRNA splicing. This protein interacts directly with the survival of motor neuron protein and it is required for formation of the SMN complex. A knockout mouse targeting the mouse homolog of this gene exhibited disrupted snRNP assembly and motor neuron degeneration. [provided by RefSeq, Aug 2011]

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=0.096943885).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003616.3. 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
	GEMIN2	NM_003616.3	MANE Select	c.585C>G	p.Asp195Glu	missense	Exon 7 of 10	NP_003607.2	O14893-5
	GEMIN2	NM_001009182.2		c.540C>G	p.Asp180Glu	missense	Exon 6 of 9	NP_001009182.2	A0A8J9FJK1
	GEMIN2	NM_001009183.2		c.585C>G	p.Asp195Glu	missense	Exon 7 of 9	NP_001009183.2	A0A8J9FN78

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GEMIN2	ENST00000308317.12	TSL:1 MANE Select	c.585C>G	p.Asp195Glu	missense	Exon 7 of 10	ENSP00000308533.7	O14893-5
	GEMIN2	ENST00000250379.13	TSL:1	c.540C>G	p.Asp180Glu	missense	Exon 6 of 9	ENSP00000250379.9	A0A8J9FJK1
	GEMIN2	ENST00000396249.7	TSL:1	c.585C>G	p.Asp195Glu	missense	Exon 7 of 9	ENSP00000379548.3	A0A8J9FN78

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1411006 Hom.: 0 Cov.: 25 AF XY: 0.00000426 AC XY: 3 AN XY: 704932

African (AFR) AF: 0.00 AC: 0 AN: 32124

American (AMR) AF: 0.00 AC: 0 AN: 42866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25760

East Asian (EAS) AF: 0.00 AC: 0 AN: 39422

South Asian (SAS) AF: 0.00 AC: 0 AN: 83486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00000280 AC: 3 AN: 1071834

Other (OTH) AF: 0.00 AC: 0 AN: 58710

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

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	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.60
DEOGEN2	Benign	0.039	T
Eigen	Benign	0.0081
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.095	N
PhyloP100		0.058
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.10
Sift	Benign	0.65	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.31		Gain of catalytic residue at L211 (P = 0.0403)
MVP		0.60
MPC		0.14
ClinPred		0.59	D
GERP RS		4.0
Varity_R		0.30
gMVP		0.052
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1015471843; hg19: chr14-39597537;