rs138428684

Variant names:

• chr14-102041574-C-G
• rs138428684
• NM_001376.5:c.11942C>G

Your query was ambiguous. Multiple possible variants found:

• chr14-102041574-C-G
• chr14-102041574-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001376.5(DYNC1H1):​c.11942C>G​(p.Thr3981Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00398 in 1,614,062 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3981T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (17 hom.)
• Consequence: DYNC1H1 NM_001376.5 missense, splice_region
• Scores: Splicing: ADA: 0.9585
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 6.11
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00933224).
• BP6: Variant 14-102041574-C-G is Benign according to our data. Variant chr14-102041574-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198352.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 = 0.00272 (414/152334) while in subpopulation NFE AF = 0.00454 (309/68022). AF 95% confidence interval is 0.00413. There are 1 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 414 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.11942C>G	p.Thr3981Arg	missense splice_region	Exon 65 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.11942C>G	p.Thr3981Arg	missense splice_region	Exon 65 of 78	ENSP00000348965.4
	DYNC1H1	ENST00000681574.1		c.11942C>G	p.Thr3981Arg	missense splice_region	Exon 65 of 77	ENSP00000505523.1
	DYNC1H1	ENST00000679720.1		c.11942C>G	p.Thr3981Arg	missense splice_region	Exon 65 of 78	ENSP00000505938.1

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00454

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00310 AC: 779 AN: 251168 AF XY: 0.00306

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00411 AC: 6003 AN: 1461728 Hom.: 17 Cov.: 31 AF XY: 0.00400 AC XY: 2908 AN XY: 727154

African (AFR) AF: 0.00125 AC: 42 AN: 33472

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 87 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86246

European-Finnish (FIN) AF: 0.00155 AC: 83 AN: 53404

Middle Eastern (MID) AF: 0.00442 AC: 25 AN: 5660

European-Non Finnish (NFE) AF: 0.00490 AC: 5444 AN: 1112006

Other (OTH) AF: 0.00379 AC: 229 AN: 60380

GnomAD4 genome AF: 0.00272 AC: 414 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74494

African (AFR) AF: 0.000890 AC: 37 AN: 41590

American (AMR) AF: 0.00157 AC: 24 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00454 AC: 309 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00477 Hom.: 2

Bravo AF: 0.00292

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00341 AC: 414

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00522

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	-	4	not specified (4)
-	-	2	Charcot-Marie-Tooth disease axonal type 2O (2)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2O;C3281202:Intellectual disability, autosomal dominant 13;C5780022:Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (1)
-	-	1	DYNC1H1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.24
Sift	Benign	0.16	T
Polyphen		0.98	D
Vest4		0.65
MVP		0.51
MPC		1.1
ClinPred		0.028	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.92
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.65
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: rs138428684; hg19: chr14-102507911;