19-45614697-T-A

Position:

• chr19-45614697-T-A

Variant summary

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

The NM_012155.4(EML2):​c.1601A>T​(p.Asp534Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: EML2 NM_012155.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EML2	NM_012155.4	c.1601A>T	p.Asp534Val	missense_variant	17/19	ENST00000245925.8	NP_036287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EML2	ENST00000245925.8	c.1601A>T	p.Asp534Val	missense_variant	17/19	1	NM_012155.4	ENSP00000245925	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461490 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727054

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.2204A>T (p.D735V) alteration is located in exon 20 (coding exon 20) of the EML2 gene. This alteration results from a A to T substitution at nucleotide position 2204, causing the aspartic acid (D) at amino acid position 735 to be replaced by a valine (V). 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	0.26
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.6	.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.3	.;D;D;.
REVEL	Uncertain	0.53
Sift	Benign	0.26	.;T;T;.
Sift4G	Uncertain	0.053	T;T;T;T
Polyphen		0.037	.;B;.;.
Vest4		0.81
MutPred		0.71		Gain of ubiquitination at K539 (P = 0.0822);Gain of ubiquitination at K539 (P = 0.0822);.;.;
MVP		0.78
MPC		0.35
ClinPred		0.97	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.52

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-46117955;