NM_001376.5:c.3015+18C>T

Variant names:

• chr14-101991691-C-T
• rs2749894
• NM_001376.5:c.3015+18C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001376.5(DYNC1H1):​c.3015+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,613,702 control chromosomes in the GnomAD database, including 9,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (3138 hom., cov: 32)
  • Exomes 𝑓: 0.078 (6320 hom.)
• Consequence: DYNC1H1 NM_001376.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.11
• Publications: 5 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: Genomics England PanelApp, Orphanet, G2P
• intellectual disability, autosomal dominant 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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: Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-101991691-C-T is Benign according to our data. Variant chr14-101991691-C-T is described in ClinVar as Benign. ClinVar VariationId is 137182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	NM_001376.5	MANE Select	c.3015+18C>T		intron	N/A	NP_001367.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	ENST00000360184.10	TSL:1 MANE Select	c.3015+18C>T		intron	N/A	ENSP00000348965.4	Q14204
	DYNC1H1	ENST00000681574.1		c.3015+18C>T		intron	N/A	ENSP00000505523.1	A0A7P0T9C4
	DYNC1H1	ENST00000679720.1		c.3015+18C>T		intron	N/A	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23331 AN: 151978 Hom.: 3130 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0833

Gnomad ASJ AF: 0.0793

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0566

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0722

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.0865 AC: 21722 AN: 251236 AF XY: 0.0808

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.0542

Gnomad ASJ exome AF: 0.0716

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0922

Gnomad NFE exome AF: 0.0748

Gnomad OTH exome AF: 0.0831

GnomAD4 exome AF: 0.0780 AC: 114066 AN: 1461606 Hom.: 6320 Cov.: 33 AF XY: 0.0768 AC XY: 55857 AN XY: 727122

African (AFR) AF: 0.377 AC: 12619 AN: 33462

American (AMR) AF: 0.0579 AC: 2588 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 1890 AN: 26132

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39696

South Asian (SAS) AF: 0.0661 AC: 5701 AN: 86234

European-Finnish (FIN) AF: 0.0939 AC: 5013 AN: 53380

Middle Eastern (MID) AF: 0.0986 AC: 568 AN: 5762

European-Non Finnish (NFE) AF: 0.0722 AC: 80312 AN: 1111832

Other (OTH) AF: 0.0889 AC: 5366 AN: 60384

GnomAD4 genome AF: 0.154 AC: 23375 AN: 152096 Hom.: 3138 Cov.: 32 AF XY: 0.151 AC XY: 11195 AN XY: 74366

African (AFR) AF: 0.366 AC: 15157 AN: 41436

American (AMR) AF: 0.0831 AC: 1271 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0793 AC: 275 AN: 3466

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0567 AC: 273 AN: 4816

European-Finnish (FIN) AF: 0.104 AC: 1103 AN: 10578

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0722 AC: 4913 AN: 68018

Other (OTH) AF: 0.139 AC: 294 AN: 2108

Alfa AF: 0.0985 Hom.: 656

Bravo AF: 0.162

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2O (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.062
DANN	Benign	0.42
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2749894; hg19: chr14-102458028;