NM_012155.4:c.1412A>C

Variant names:

• chr19-45616558-T-G
• NM_012155.4:c.1412A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012155.4(EML2):​c.1412A>C​(p.Asp471Ala) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EML2 NM_012155.4 missense, splice_region
• Scores: Splicing: ADA: 0.1367
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71
• Publications: 0 publications found

Genes affected

EML2 (HGNC:18035): (EMAP like 2) Enables microtubule binding activity. Involved in negative regulation of microtubule polymerization and regulation of microtubule nucleation. Colocalizes with mitotic spindle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012155.4. 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
	EML2	NM_012155.4	MANE Select	c.1412A>C	p.Asp471Ala	missense splice_region	Exon 15 of 19	NP_036287.1	O95834-1
	EML2	NM_001193268.3		c.2015A>C	p.Asp672Ala	missense splice_region	Exon 18 of 22	NP_001180197.1	O95834-3
	EML2	NM_001352052.1		c.2012A>C	p.Asp671Ala	missense splice_region	Exon 18 of 22	NP_001338981.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EML2	ENST00000245925.8	TSL:1 MANE Select	c.1412A>C	p.Asp471Ala	missense splice_region	Exon 15 of 19	ENSP00000245925.3	O95834-1
	EML2	ENST00000589876.5	TSL:1	c.1412A>C	p.Asp471Ala	missense splice_region	Exon 15 of 19	ENSP00000464789.1	K7EIK7
	EML2	ENST00000587152.6	TSL:2	c.2015A>C	p.Asp672Ala	missense splice_region	Exon 18 of 22	ENSP00000468312.1	O95834-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.68	P
Vest4		0.66
MutPred		0.58		Loss of phosphorylation at Y474 (P = 0.0887)
MVP		0.87
MPC		0.44
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		2.7
Varity_R		0.81
gMVP		0.72
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.14
dbscSNV1_RF	Benign	0.56
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

hg19: chr19-46119816;