2-84518017-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_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. 14/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DNAH6
• BP4: Computational evidence support a benign effect (MetaRNN=0.16276288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH6	NM_001370.2	c.191G>C	p.Arg64Thr	missense_variant	2/77	ENST00000389394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH6	ENST00000389394.8	c.191G>C	p.Arg64Thr	missense_variant	2/77	5	NM_001370.2	P1
DNAH6	ENST00000494025.1	n.195G>C		non_coding_transcript_exon_variant	1/9	1
DNAH6	ENST00000468661.1	n.246G>C		non_coding_transcript_exon_variant	2/4	4
DNAH6	ENST00000476689.5	n.328G>C		non_coding_transcript_exon_variant	2/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000125 AC: 17 AN: 1362118 Hom.: 0 Cov.: 31 AF XY: 0.0000149 AC XY: 10 AN XY: 672854

Gnomad4 AFR exome AF: 0.0000333

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000309

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000891

Gnomad4 NFE exome AF: 0.00000945

Gnomad4 OTH exome AF: 0.0000180

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2021

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	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Benign	0.0096	T;T
Eigen	Benign	0.018
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	T;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Benign	0.48	T
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	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-84745141;