2-84797607-C-T

Variant names:

• chr2-84797607-C-T
• rs1192395
• NM_001370.2:c.11430C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001370.2(DNAH6):​c.11430C>T​(p.Ile3810Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,550,648 control chromosomes in the GnomAD database, including 12,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1160 hom., cov: 32)
  • Exomes 𝑓: 0.13 (11474 hom.)
• Consequence: DNAH6 NM_001370.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.58
• Publications: 12 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 2-84797607-C-T is Benign according to our data. Variant chr2-84797607-C-T is described in ClinVar as Benign. ClinVar VariationId is 402746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH6	NM_001370.2	MANE Select	c.11430C>T	p.Ile3810Ile	synonymous	Exon 70 of 77	NP_001361.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH6	ENST00000389394.8	TSL:5 MANE Select	c.11430C>T	p.Ile3810Ile	synonymous	Exon 70 of 77	ENSP00000374045.3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18632 AN: 152050 Hom.: 1159 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0786

Gnomad SAS AF: 0.0877

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.124 AC: 19401 AN: 157092 AF XY: 0.121

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0772

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.125 AC: 174910 AN: 1398480 Hom.: 11474 Cov.: 31 AF XY: 0.124 AC XY: 85741 AN XY: 689776

African (AFR) AF: 0.110 AC: 3463 AN: 31580

American (AMR) AF: 0.153 AC: 5442 AN: 35670

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 3839 AN: 25148

East Asian (EAS) AF: 0.0722 AC: 2578 AN: 35718

South Asian (SAS) AF: 0.0939 AC: 7434 AN: 79146

European-Finnish (FIN) AF: 0.142 AC: 7020 AN: 49264

Middle Eastern (MID) AF: 0.127 AC: 726 AN: 5698

European-Non Finnish (NFE) AF: 0.127 AC: 137297 AN: 1078246

Other (OTH) AF: 0.123 AC: 7111 AN: 58010

GnomAD4 genome AF: 0.122 AC: 18640 AN: 152168 Hom.: 1160 Cov.: 32 AF XY: 0.121 AC XY: 9020 AN XY: 74398

African (AFR) AF: 0.115 AC: 4771 AN: 41524

American (AMR) AF: 0.117 AC: 1784 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 525 AN: 3468

East Asian (EAS) AF: 0.0780 AC: 405 AN: 5190

South Asian (SAS) AF: 0.0871 AC: 420 AN: 4820

European-Finnish (FIN) AF: 0.144 AC: 1526 AN: 10580

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8598 AN: 67976

Other (OTH) AF: 0.132 AC: 280 AN: 2114

Alfa AF: 0.121 Hom.: 2209

Bravo AF: 0.122

Asia WGS AF: 0.0980 AC: 341 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	DNAH6-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.5
DANN	Benign	0.66
PhyloP100		1.6
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1192395; hg19: chr2-85024731; COSMIC: COSV52861533;