chr2-84517989-C-T

Position:

• chr2-84517989-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001370.2(DNAH6):​c.163C>T​(p.His55Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00926 in 1,550,482 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (71 hom.)
• Consequence: DNAH6 NM_001370.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.53

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNAH6. . Gene score misZ 3.5535 (greater than the threshold 3.09). Trascript score misZ 3.4022 (greater than threshold 3.09). GenCC has associacion of gene with male infertility with azoospermia or oligozoospermia due to single gene mutation.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0042708516).
• BP6: Variant 2-84517989-C-T is Benign according to our data. Variant chr2-84517989-C-T is described in ClinVar as [Benign]. Clinvar id is 782980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.163C>T	p.His55Tyr	missense_variant	2/77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.163C>T	p.His55Tyr	missense_variant	2/77	5	NM_001370.2	ENSP00000374045.3
DNAH6	ENST00000494025.1	n.167C>T		non_coding_transcript_exon_variant	1/9	1
DNAH6	ENST00000468661.1	n.218C>T		non_coding_transcript_exon_variant	2/4	4
DNAH6	ENST00000476689.5	n.300C>T		non_coding_transcript_exon_variant	2/11	2

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1093 AN: 152094 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00649 AC: 1026 AN: 158184 Hom.: 4 AF XY: 0.00611 AC XY: 510 AN XY: 83424

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00599

Gnomad ASJ exome AF: 0.00293

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000264

Gnomad FIN exome AF: 0.00960

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.00984

GnomAD4 exome AF: 0.00949 AC: 13272 AN: 1398268 Hom.: 71 Cov.: 31 AF XY: 0.00907 AC XY: 6254 AN XY: 689678

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.00740

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000391

Gnomad4 FIN exome AF: 0.00865

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00887

GnomAD4 genome AF: 0.00718 AC: 1093 AN: 152214 Hom.: 7 Cov.: 32 AF XY: 0.00705 AC XY: 525 AN XY: 74440

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.00996

Alfa AF: 0.00927 Hom.: 9

Bravo AF: 0.00701

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00974 AC: 31

ExAC AF: 0.00452 AC: 114

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DNAH6: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

DNAH6-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.59	T;.
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.051
Sift	Uncertain	0.0080	D;D
Polyphen		0.82	P;P
Vest4		0.31
MVP		0.27
MPC		0.14
ClinPred		0.031	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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

Other links and lift over

dbSNP: rs112166113; hg19: chr2-84745113;