NM_001376.5:c.2719-130G>C

Variant names:

• chr14-101988573-G-C
• rs12161908
• NM_001376.5:c.2719-130G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001376.5(DYNC1H1):​c.2719-130G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,173,818 control chromosomes in the GnomAD database, including 119 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 0.0059 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (102 hom.)
• Consequence: DYNC1H1 NM_001376.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.228
• Publications: 1 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0059 (899/152294) while in subpopulation EAS AF = 0.0367 (190/5182). AF 95% confidence interval is 0.0324. There are 17 homozygotes in GnomAd4. There are 481 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 899 AD gene.

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.2719-130G>C		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.2719-130G>C		intron	N/A	ENSP00000348965.4
	DYNC1H1	ENST00000681321.1		n.858G>C		non_coding_transcript_exon	Exon 3 of 3
	DYNC1H1	ENST00000681574.1		c.2719-130G>C		intron	N/A	ENSP00000505523.1

Frequencies

GnomAD3 genomes AF: 0.00583 AC: 887 AN: 152176 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0362

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00441 AC: 4508 AN: 1021524 Hom.: 102 AF XY: 0.00440 AC XY: 2288 AN XY: 519600

African (AFR) AF: 0.00283 AC: 69 AN: 24412

American (AMR) AF: 0.0462 AC: 1642 AN: 35554

Ashkenazi Jewish (ASJ) AF: 0.000975 AC: 22 AN: 22556

East Asian (EAS) AF: 0.0373 AC: 1303 AN: 34898

South Asian (SAS) AF: 0.0146 AC: 1058 AN: 72688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37022

Middle Eastern (MID) AF: 0.00835 AC: 40 AN: 4790

European-Non Finnish (NFE) AF: 0.000218 AC: 162 AN: 744130

Other (OTH) AF: 0.00466 AC: 212 AN: 45474

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152294 Hom.: 17 Cov.: 32 AF XY: 0.00646 AC XY: 481 AN XY: 74470

African (AFR) AF: 0.00301 AC: 125 AN: 41552

American (AMR) AF: 0.0295 AC: 452 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.0367 AC: 190 AN: 5182

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00281 Hom.: 3

Bravo AF: 0.00769

Asia WGS AF: 0.0270 AC: 92 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.47
DANN	Benign	0.39
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

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: rs12161908; hg19: chr14-102454910;