Genetic Variant DNAH6:p.Val80Ala (chr2-84525578-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001370.2(DNAH6):c.239T>C(p.Val80Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,392,606 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DNAH6
NM_001370.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056701273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2 link	c.239T>C	p.Val80Ala	missense_variant	Exon 3 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.239T>C	p.Val80Ala	missense_variant	Exon 3 of 77	5	NM_001370.2	ENSP00000374045.3	Q9C0G6-1
DNAH6	ENST00000494025.1 link	n.229+7527T>C		intron_variant	Intron 1 of 8	1
DNAH6	ENST00000468661.1 link	n.294T>C		non_coding_transcript_exon_variant	Exon 3 of 4	4
DNAH6	ENST00000476689.5 link	n.376T>C		non_coding_transcript_exon_variant	Exon 3 of 11	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1392606

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686600

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:

31104

American (AMR)

AF:

0.00

AC:

AN:

33856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24968

East Asian (EAS)

AF:

0.00

AC:

AN:

35596

South Asian (SAS)

AF:

0.00

AC:

AN:

77514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1076888

Other (OTH)

AF:

0.0000346

AC:

AN:

57768

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 26, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.239T>C (p.V80A) alteration is located in exon 3 (coding exon 2) of the DNAH6 gene. This alteration results from a T to C substitution at nucleotide position 239, causing the valine (V) at amino acid position 80 to be replaced by an alanine (A). 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

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0066

T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.38

T;.

M_CAP

Benign

0.0042

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.0

L;L

PhyloP100

1.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.43

N;N

REVEL

Benign

0.064

Sift

Benign

0.22

T;T

Polyphen

0.0

B;B

Vest4

0.093

MVP

0.17

MPC

0.098

ClinPred

0.063

GERP RS

0.55

Varity_R

0.040

gMVP

0.12

Mutation Taster

=77/23

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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2-84525578-T-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