2-84528872-ATTT-ATTTTTTTT

Variant names:

• chr2-84528872-A-ATTTTT
• rs67469465
• NM_001370.2:c.400-25_400-21dupTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001370.2(DNAH6):​c.400-25_400-21dupTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,180,712 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000093 (0 hom.)
• Consequence: DNAH6 NM_001370.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.797
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.400-25_400-21dupTTTTT		intron_variant	Intron 3 of 76	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8	c.400-32_400-31insTTTTT		intron_variant	Intron 3 of 76	5	NM_001370.2	ENSP00000374045.3
DNAH6	ENST00000494025.1	n.229+10821_229+10822insTTTTT		intron_variant	Intron 1 of 8	1
DNAH6	ENST00000468661.1	n.454+3134_454+3135insTTTTT		intron_variant	Intron 3 of 3	4
DNAH6	ENST00000476689.5	n.536+3134_536+3135insTTTTT		intron_variant	Intron 3 of 10	2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000932 AC: 11 AN: 1180712 Hom.: 0 Cov.: 33 AF XY: 0.00000517 AC XY: 3 AN XY: 579820

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

African (AFR) AF: 0.00 AC: 0 AN: 24208

American (AMR) AF: 0.0000458 AC: 1 AN: 21836

Ashkenazi Jewish (ASJ) AF: 0.0000503 AC: 1 AN: 19892

East Asian (EAS) AF: 0.00 AC: 0 AN: 27986

South Asian (SAS) AF: 0.00 AC: 0 AN: 61750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4796

European-Non Finnish (NFE) AF: 0.00000859 AC: 8 AN: 931206

Other (OTH) AF: 0.0000207 AC: 1 AN: 48354

⚠️ 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.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.80
La Branchor		0.96
BranchPoint Hunter		6.0

Splicing

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

Other links and lift over

dbSNP: rs67469465; hg19: chr2-84755996;