Genetic Variant NM_001387690.1:c.479G>C (chr18-47059584-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001387690.1(KATNAL2):c.479G>C(p.Ser160Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S160N) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KATNAL2
NM_001387690.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.903

Publications

0 publications found

Variant links:

Genes affected

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KATNAL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09834507).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387690.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KATNAL2	NM_001387690.1	MANE Select	c.479G>C	p.Ser160Thr	missense	Exon 8 of 18	NP_001374619.1
KATNAL2	NM_001353899.1		c.557G>C	p.Ser186Thr	missense	Exon 8 of 18	NP_001340828.1
KATNAL2	NM_001353900.1		c.554G>C	p.Ser185Thr	missense	Exon 8 of 18	NP_001340829.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KATNAL2	ENST00000683218.1	MANE Select	c.479G>C	p.Ser160Thr	missense	Exon 8 of 18	ENSP00000508137.1
KATNAL2	ENST00000245121.10	TSL:1	c.263G>C	p.Ser88Thr	missense	Exon 7 of 17	ENSP00000245121.4
KATNAL2	ENST00000591522.2	TSL:1	c.146G>C	p.Ser49Thr	missense	Exon 5 of 12	ENSP00000467488.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460426

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726648

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110744

Other (OTH)

AF:

0.00

AC:

AN:

60320

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Benign

0.30

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.050

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.44

M_CAP

Benign

0.046

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.6

PhyloP100

-0.90

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

REVEL

Benign

0.13

Sift

Benign

0.053

Sift4G

Uncertain

0.060

Polyphen

0.012

Vest4

0.17

MutPred

0.24

Loss of disorder (P = 0.0923)

MVP

0.57

MPC

0.10

ClinPred

0.064

GERP RS

-4.8

Varity_R

0.084

gMVP

0.50

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over