2-84528872-ATTT-ATTTTTT

Variant names:

• chr2-84528872-A-ATTT
• rs67469465
• NM_001370.2:c.400-23_400-21dupTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001370.2(DNAH6):​c.400-23_400-21dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 1,304,062 control chromosomes in the GnomAD database, including 244 homozygotes. 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: 𝑓 0.027 (92 hom., cov: 0)
  • Exomes 𝑓: 0.047 (152 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2	c.400-23_400-21dupTTT		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_400-31insTTT		intron_variant	Intron 3 of 76	5	NM_001370.2	ENSP00000374045.3
DNAH6	ENST00000494025.1	n.229+10821_229+10822insTTT		intron_variant	Intron 1 of 8	1
DNAH6	ENST00000468661.1	n.454+3134_454+3135insTTT		intron_variant	Intron 3 of 3	4
DNAH6	ENST00000476689.5	n.536+3134_536+3135insTTT		intron_variant	Intron 3 of 10	2

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4078 AN: 148486 Hom.: 92 Cov.: 0

Gnomad AFR AF: 0.00586

Gnomad AMI AF: 0.00773

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.0344

Gnomad EAS AF: 0.000595

Gnomad SAS AF: 0.0585

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.0609

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0360

GnomAD2 exomes AF: 0.0482 AC: 4391 AN: 91098 AF XY: 0.0527

Gnomad AFR exome AF: 0.00619

Gnomad AMR exome AF: 0.0379

Gnomad ASJ exome AF: 0.0540

Gnomad EAS exome AF: 0.00791

Gnomad FIN exome AF: 0.0476

Gnomad NFE exome AF: 0.0532

Gnomad OTH exome AF: 0.0475

GnomAD4 exome AF: 0.0470 AC: 54357 AN: 1155490 Hom.: 152 Cov.: 33 AF XY: 0.0483 AC XY: 27415 AN XY: 567302

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

African (AFR) AF: 0.00809 AC: 195 AN: 24096

American (AMR) AF: 0.0330 AC: 711 AN: 21548

Ashkenazi Jewish (ASJ) AF: 0.0482 AC: 941 AN: 19522

East Asian (EAS) AF: 0.00353 AC: 98 AN: 27776

South Asian (SAS) AF: 0.0749 AC: 4544 AN: 60654

European-Finnish (FIN) AF: 0.0438 AC: 1742 AN: 39756

Middle Eastern (MID) AF: 0.0757 AC: 360 AN: 4756

European-Non Finnish (NFE) AF: 0.0480 AC: 43631 AN: 909894

Other (OTH) AF: 0.0450 AC: 2135 AN: 47488

⚠️ 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 AF: 0.0274 AC: 4075 AN: 148572 Hom.: 92 Cov.: 0 AF XY: 0.0279 AC XY: 2012 AN XY: 72100

African (AFR) AF: 0.00584 AC: 236 AN: 40404

American (AMR) AF: 0.0388 AC: 580 AN: 14936

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 119 AN: 3456

East Asian (EAS) AF: 0.000596 AC: 3 AN: 5030

South Asian (SAS) AF: 0.0580 AC: 269 AN: 4634

European-Finnish (FIN) AF: 0.0290 AC: 275 AN: 9488

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.0370 AC: 2493 AN: 67354

Other (OTH) AF: 0.0357 AC: 74 AN: 2072

Alfa AF: 0.0303 Hom.: 396

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
Mutation Taster		=100/0	polymorphism

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;