rs199763298

Variant names:

• chr14-101988697-C-T
• rs199763298
• NM_001376.5:c.2719-6C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001376.5(DYNC1H1):​c.2719-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,982 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: DYNC1H1 NM_001376.5 splice_region, intron
• Scores: Splicing: ADA: 0.001758
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.718
• 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: 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 14-101988697-C-T is Benign according to our data. Variant chr14-101988697-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000743 (113/152148) while in subpopulation NFE AF = 0.00131 (89/68040). AF 95% confidence interval is 0.00109. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 113 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	NM_001376.5	MANE Select	c.2719-6C>T		splice_region 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.2719-6C>T		splice_region intron	N/A	ENSP00000348965.4	Q14204
	DYNC1H1	ENST00000681574.1		c.2719-6C>T		splice_region intron	N/A	ENSP00000505523.1	A0A7P0T9C4
	DYNC1H1	ENST00000679720.1		c.2719-6C>T		splice_region intron	N/A	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000804 AC: 202 AN: 251310 AF XY: 0.000802

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00144 AC: 2101 AN: 1461834 Hom.: 4 Cov.: 31 AF XY: 0.00134 AC XY: 975 AN XY: 727224

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000559 AC: 25 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53404

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00179 AC: 1990 AN: 1112000

Other (OTH) AF: 0.000944 AC: 57 AN: 60396

GnomAD4 genome AF: 0.000743 AC: 113 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000619 AC XY: 46 AN XY: 74328

African (AFR) AF: 0.000338 AC: 14 AN: 41418

American (AMR) AF: 0.000262 AC: 4 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.000941

EpiCase AF: 0.00147

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	Charcot-Marie-Tooth disease axonal type 2O (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	8.0
DANN	Benign	0.89
PhyloP100		0.72
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.080
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: rs199763298; hg19: chr14-102455034;