14-102041124-A-G

Variant names:

• chr14-102041124-A-G
• rs941793
• NM_001376.5:c.11942-450A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001376.5(DYNC1H1):​c.11942-450A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 338,510 control chromosomes in the GnomAD database, including 18,938 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.35 (12362 hom., cov: 32)
  • Exomes 𝑓: 0.25 (6576 hom.)
• Consequence: DYNC1H1 NM_001376.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.470
• Publications: 2 publications found

Genes affected

DYNC1H1 (HGNC:2961): (dynein cytoplasmic 1 heavy chain 1) Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains.This gene encodes a member of the cytoplasmic dynein heavy chain family. [provided by RefSeq, Oct 2008]

DYNC1H1 Gene-Disease associations (from GenCC):

• autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
• intellectual disability, autosomal dominant 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• neuronopathy, distal hereditary motor

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2O

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000293472 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376.5. 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
	DYNC1H1	NM_001376.5	MANE Select	c.11942-450A>G		intron	N/A	NP_001367.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	ENST00000360184.10	TSL:1 MANE Select	c.11942-450A>G		intron	N/A	ENSP00000348965.4
	DYNC1H1	ENST00000556499.3	TSL:3	n.625A>G		non_coding_transcript_exon	Exon 2 of 5
	DYNC1H1	ENST00000681574.1		c.11942-450A>G		intron	N/A	ENSP00000505523.1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53803 AN: 151910 Hom.: 12322 Cov.: 32

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.359

GnomAD4 exome AF: 0.248 AC: 46322 AN: 186482 Hom.: 6576 Cov.: 0 AF XY: 0.249 AC XY: 24972 AN XY: 100452

African (AFR) AF: 0.662 AC: 3652 AN: 5514

American (AMR) AF: 0.287 AC: 2271 AN: 7904

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 1262 AN: 4740

East Asian (EAS) AF: 0.278 AC: 2170 AN: 7804

South Asian (SAS) AF: 0.272 AC: 9122 AN: 33586

European-Finnish (FIN) AF: 0.217 AC: 1886 AN: 8708

Middle Eastern (MID) AF: 0.307 AC: 199 AN: 648

European-Non Finnish (NFE) AF: 0.216 AC: 23325 AN: 108176

Other (OTH) AF: 0.259 AC: 2435 AN: 9402

GnomAD4 genome AF: 0.355 AC: 53904 AN: 152028 Hom.: 12362 Cov.: 32 AF XY: 0.349 AC XY: 25964 AN XY: 74312

African (AFR) AF: 0.663 AC: 27475 AN: 41442

American (AMR) AF: 0.296 AC: 4522 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 926 AN: 3470

East Asian (EAS) AF: 0.275 AC: 1425 AN: 5176

South Asian (SAS) AF: 0.282 AC: 1355 AN: 4812

European-Finnish (FIN) AF: 0.228 AC: 2405 AN: 10564

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14839 AN: 67978

Other (OTH) AF: 0.355 AC: 751 AN: 2114

Alfa AF: 0.285 Hom.: 1940

Bravo AF: 0.373

Asia WGS AF: 0.285 AC: 990 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.5
DANN	Benign	0.49
PhyloP100		0.47
Mutation Taster		=100/0	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: rs941793; hg19: chr14-102507461;