rs2273437

Variant names:

• chr14-101964737-T-C
• rs2273437
• NM_001376.5:c.46T>C
• DYNC1H1 p.Leu16Leu

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001376.5(DYNC1H1):​c.46T>C​(p.Leu16Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,596,858 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (117 hom.)
• Consequence: DYNC1H1 NM_001376.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.820
• 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: G2P, Orphanet, Genomics England PanelApp
• intellectual disability, autosomal dominant 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 14-101964737-T-C is Benign according to our data. Variant chr14-101964737-T-C is described in ClinVar as Benign. ClinVar VariationId is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00551 (837/151990) while in subpopulation EAS AF = 0.0365 (188/5146). AF 95% confidence interval is 0.0323. There are 17 homozygotes in GnomAd4. There are 451 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 837 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.46T>C	p.Leu16Leu	synonymous	Exon 1 of 78	NP_001367.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	ENST00000360184.10	TSL:1 MANE Select	c.46T>C	p.Leu16Leu	synonymous	Exon 1 of 78	ENSP00000348965.4	Q14204
	DYNC1H1	ENST00000681574.1		c.46T>C	p.Leu16Leu	synonymous	Exon 1 of 77	ENSP00000505523.1	A0A7P0T9C4
	DYNC1H1	ENST00000679720.1		c.46T>C	p.Leu16Leu	synonymous	Exon 1 of 78	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 824 AN: 151872 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0361

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00480

GnomAD2 exomes AF: 0.0122 AC: 2653 AN: 216820 AF XY: 0.0103

Gnomad AFR exome AF: 0.000980

Gnomad AMR exome AF: 0.0495

Gnomad ASJ exome AF: 0.000847

Gnomad EAS exome AF: 0.0327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000298

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00361 AC: 5209 AN: 1444868 Hom.: 117 Cov.: 31 AF XY: 0.00358 AC XY: 2569 AN XY: 718432

African (AFR) AF: 0.00141 AC: 47 AN: 33254

American (AMR) AF: 0.0461 AC: 2018 AN: 43728

Ashkenazi Jewish (ASJ) AF: 0.000965 AC: 25 AN: 25912

East Asian (EAS) AF: 0.0366 AC: 1433 AN: 39136

South Asian (SAS) AF: 0.0137 AC: 1168 AN: 85118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44424

Middle Eastern (MID) AF: 0.00749 AC: 43 AN: 5742

European-Non Finnish (NFE) AF: 0.000190 AC: 211 AN: 1107738

Other (OTH) AF: 0.00441 AC: 264 AN: 59816

GnomAD4 genome AF: 0.00551 AC: 837 AN: 151990 Hom.: 17 Cov.: 32 AF XY: 0.00607 AC XY: 451 AN XY: 74348

African (AFR) AF: 0.00183 AC: 76 AN: 41468

American (AMR) AF: 0.0294 AC: 450 AN: 15284

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

East Asian (EAS) AF: 0.0365 AC: 188 AN: 5146

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67930

Other (OTH) AF: 0.00475 AC: 10 AN: 2106

Alfa AF: 0.00155 Hom.: 3

Bravo AF: 0.00727

Asia WGS AF: 0.0250 AC: 85 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Charcot-Marie-Tooth disease axonal type 2O (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	-0.60
CADD	Benign	14
DANN	Benign	0.66
PhyloP100		0.82
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2273437;

hg19: chr14-102431074;

COSMIC: COSV64135190;

COSMIC: COSV64135190;