19-45616549-T-C

Variant names:

• chr19-45616549-T-C
• rs1171431268
• NM_012155.4:c.1421A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012155.4(EML2):​c.1421A>G​(p.Tyr474Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EML2 NM_012155.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EML2	NM_012155.4	c.1421A>G	p.Tyr474Cys	missense_variant	Exon 15 of 19	ENST00000245925.8	NP_036287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EML2	ENST00000245925.8	c.1421A>G	p.Tyr474Cys	missense_variant	Exon 15 of 19	1	NM_012155.4	ENSP00000245925.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 245092 Hom.: 0 AF XY: 0.00000748 AC XY: 1 AN XY: 133742

Gnomad AFR exome AF: 0.0000665

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458238 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724902

Gnomad4 AFR exome AF: 0.0000299

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2024A>G (p.Y675C) alteration is located in exon 18 (coding exon 18) of the EML2 gene. This alteration results from a A to G substitution at nucleotide position 2024, causing the tyrosine (Y) at amino acid position 675 to be replaced by a cysteine (C). 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	0.090
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T;T;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.69	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.7	.;M;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.4	.;D;D;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	.;D;D;.;.
Sift4G	Uncertain	0.021	D;T;D;D;T
Polyphen		0.98	.;D;.;.;.
Vest4		0.75
MutPred		0.53		Loss of phosphorylation at Y474 (P = 0.0221);Loss of phosphorylation at Y474 (P = 0.0221);.;.;.;
MVP		0.70
MPC		0.32
ClinPred		0.74	D
GERP RS		3.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.53
gMVP		0.51

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: rs1171431268; hg19: chr19-46119807;