2-84528925-G-C

Variant names:

• chr2-84528925-G-C
• rs4832089
• NM_001370.2:c.421G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001370.2(DNAH6):​c.421G>C​(p.Val141Leu) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V141M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 25)
• Consequence: DNAH6 NM_001370.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

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=0.045072824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.421G>C	p.Val141Leu	missense_variant	Exon 4 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.421G>C	p.Val141Leu	missense_variant	Exon 4 of 77	5	NM_001370.2	ENSP00000374045.3
DNAH6	ENST00000494025.1	n.229+10874G>C		intron_variant	Intron 1 of 8	1
DNAH6	ENST00000468661.1	n.454+3187G>C		intron_variant	Intron 3 of 3	4
DNAH6	ENST00000476689.5	n.536+3187G>C		intron_variant	Intron 3 of 10	2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0030
DANN	Benign	0.58
DEOGEN2	Benign	0.0079	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.37	T;.
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N;N
PhyloP100		-1.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.33	N;N
REVEL	Benign	0.0020
Sift	Benign	0.36	T;T
Polyphen		0.0	B;B
Vest4		0.079
MutPred		0.23		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.10
MPC		0.079
ClinPred		0.14	T
GERP RS		-5.8
Varity_R		0.036
gMVP		0.14
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4832089; hg19: chr2-84756049;