NM_003616.3:c.172G>C

Variant names:

• chr14-39114863-G-C
• rs2052480675
• NM_003616.3:c.172G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003616.3(GEMIN2):​c.172G>C​(p.Ala58Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GEMIN2 NM_003616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37

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]

LOC105370459 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN2	NM_003616.3	c.172G>C	p.Ala58Pro	missense_variant	Exon 2 of 10	ENST00000308317.12	NP_003607.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEMIN2	ENST00000308317.12	c.172G>C	p.Ala58Pro	missense_variant	Exon 2 of 10	1	NM_003616.3	ENSP00000308533.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.205G>C (p.A69P) alteration is located in exon 2 (coding exon 2) of the GEMIN2 gene. This alteration results from a G to C substitution at nucleotide position 205, causing the alanine (A) at amino acid position 69 to be replaced by a proline (P). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Benign	0.82
DEOGEN2	Uncertain	0.66	D;.;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.5	M;M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.92
MutPred		0.72		Gain of catalytic residue at P73 (P = 0.0068);Gain of catalytic residue at P73 (P = 0.0068);Gain of catalytic residue at P73 (P = 0.0068);
MVP		0.72
MPC		0.74
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2052480675; hg19: chr14-39584067;