Genetic Variant NM_001370.2:c.191G>C (chr2-84518017-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_001370.2(DNAH6):c.191G>C(p.Arg64Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DNAH6
NM_001370.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.47

Variant links:

Genes affected

DNAH6 (HGNC:2951): (dynein axonemal heavy chain 6) This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Mutations in this gene may cause primary ciliary dyskinesia (PCD) as well as heterotaxy. [provided by RefSeq, Jun 2016]

DNAH6 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=0.16276288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2 link	c.191G>C	p.Arg64Thr	missense_variant	Exon 2 of 77	ENST00000389394.8	NP_001361.1	Q9C0G6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH6	ENST00000389394.8 link	c.191G>C	p.Arg64Thr	missense_variant	Exon 2 of 77	5	NM_001370.2	ENSP00000374045.3	Q9C0G6-1
DNAH6	ENST00000494025.1 link	n.195G>C		non_coding_transcript_exon_variant	Exon 1 of 9	1
DNAH6	ENST00000468661.1 link	n.246G>C		non_coding_transcript_exon_variant	Exon 2 of 4	4
DNAH6	ENST00000476689.5 link	n.328G>C		non_coding_transcript_exon_variant	Exon 2 of 11	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000125

AC:

AN:

1362118

Hom.:

Cov.:

AF XY:

0.0000149

AC XY:

AN XY:

672854

show subpopulations

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

African (AFR)

AF:

0.0000333

AC:

AN:

30002

American (AMR)

AF:

0.00

AC:

AN:

34416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23300

East Asian (EAS)

AF:

0.0000309

AC:

AN:

32384

South Asian (SAS)

AF:

0.00

AC:

AN:

78432

European-Finnish (FIN)

AF:

0.0000891

AC:

AN:

44870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5518

European-Non Finnish (NFE)

AF:

0.00000945

AC:

AN:

1057732

Other (OTH)

AF:

0.0000180

AC:

AN:

55464

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.237

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.191G>C (p.R64T) alteration is located in exon 2 (coding exon 1) of the DNAH6 gene. This alteration results from a G to C substitution at nucleotide position 191, causing the arginine (R) at amino acid position 64 to be replaced by a threonine (T). 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

Uncertain

0.43

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0096

T;T

Eigen

Benign

0.018

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.73

T;.

M_CAP

Benign

0.017

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;L

PhyloP100

2.5

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.10

Sift

Benign

0.030

D;D

Polyphen

0.61

P;P

Vest4

0.38

MutPred

0.31

Gain of phosphorylation at R64 (P = 0.0191);Gain of phosphorylation at R64 (P = 0.0191);

MVP

0.34

MPC

0.14

ClinPred

0.34

GERP RS

4.8

Varity_R

0.14

gMVP

0.37

Mutation Taster

=81/19

polymorphism

(source)

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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NM_001370.2:c.191G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over