chr18-47033305-T-C

Position:

• chr18-47033305-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016427.3(ELOA2):​c.1960A>G​(p.Thr654Ala) 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 1,461,276 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ELOA2 NM_016427.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.925

Genes affected

ELOA2 (HGNC:30771): (elongin A2) This gene encodes the transcriptionally active subunit of the SIII (or elongin) transcription elongation factor complex, which also includes two regulatory subunits, elongins B and C. This complex acts to increase the rate of RNA chain elongation by RNA polymerase II by suppressing transient pausing of the polymerase at many sites along the DNA template. Whereas a related protein with similar function, elongin A, is ubiquitously expressed, the encoded protein is specifically expressed in the testis, suggesting it may have a role in spermatogenesis. [provided by RefSeq, Jul 2008]

KATNAL2 (HGNC:25387): (katanin catalytic subunit A1 like 2) Predicted to enable microtubule-severing ATPase activity. Predicted to be involved in cytoplasmic microtubule organization. Located in cytoplasm; microtubule; and spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

KATNAL2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026994497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELOA2	NM_016427.3	c.1960A>G	p.Thr654Ala	missense_variant	1/1	ENST00000332567.6	NP_057511.2
KATNAL2	NM_001387690.1	c.52-13152T>C		intron_variant		ENST00000683218.1	NP_001374619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELOA2	ENST00000332567.6	c.1960A>G	p.Thr654Ala	missense_variant	1/1	6	NM_016427.3	ENSP00000331302.4
KATNAL2	ENST00000683218.1	c.52-13152T>C		intron_variant			NM_001387690.1	ENSP00000508137.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461276 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726924

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.17
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.26	T;T
M_CAP	Benign	0.00089	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.97	N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.41	N;.
REVEL	Benign	0.017
Sift	Benign	0.34	T;.
Sift4G	Benign	0.73	T;T
Polyphen		0.0	B;.
Vest4		0.018
MutPred		0.14		Loss of phosphorylation at T654 (P = 0.005);.;
MVP		0.014
MPC		0.041
ClinPred		0.22	T
GERP RS		-0.67
Varity_R		0.050
gMVP		0.20

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: rs1024953634; hg19: chr18-44559676;