Genetic Variant DNAH2:p.Leu114His (chr17-7727234-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020877.5(DNAH2):c.341T>A(p.Leu114His) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,611,820 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: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DNAH2
NM_020877.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.50

Variant links:

Genes affected

DNAH2 (HGNC:2948): (dynein axonemal heavy chain 2) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. The axonemal dyneins, found in cilia and flagella, are components of the outer and inner dynein arms attached to the peripheral microtubule doublets. DNAH2 is an axonemal inner arm dynein heavy chain (Chapelin et al., 1997 [PubMed 9256245]).[supplied by OMIM, Mar 2008]

DNAH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH2	NM_020877.5 link	c.341T>A	p.Leu114His	missense_variant	Exon 4 of 86	ENST00000572933.6	NP_065928.2	Q9P225-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH2	ENST00000572933.6 link	c.341T>A	p.Leu114His	missense_variant	Exon 4 of 86	2	NM_020877.5	ENSP00000458355.1	Q9P225-1
DNAH2	ENST00000570791.5 link	c.341T>A	p.Leu114His	missense_variant	Exon 4 of 14	1		ENSP00000460245.1	Q9P225-3
DNAH2	ENST00000389173.6 link	c.341T>A	p.Leu114His	missense_variant	Exon 3 of 85	2		ENSP00000373825.2	Q9P225-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459612

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726100

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.341T>A (p.L114H) alteration is located in exon 3 (coding exon 3) of the DNAH2 gene. This alteration results from a T to A substitution at nucleotide position 341, causing the leucine (L) at amino acid position 114 to be replaced by a histidine (H). 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

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;.;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.63

.;T;T

M_CAP

Benign

0.019

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.69

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.8

.;.;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

.;.;D

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

0.99

D;D;D

Vest4

0.78

MutPred

0.76

Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);

MVP

0.61

MPC

0.62

ClinPred

0.99

GERP RS

4.8

Varity_R

0.54

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over