rs2251644

Variant names:

• chr14-102001510-A-G
• rs2251644
• NM_001376.5:c.4396-25A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-102001510-A-G
• chr14-102001510-A-C

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.4396-25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,613,774 control chromosomes in the GnomAD database, including 20,358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4411 hom., cov: 32)
  • Exomes 𝑓: 0.13 (15947 hom.)
• Consequence: DYNC1H1 NM_001376.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.28
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 14-102001510-A-G is Benign according to our data. Variant chr14-102001510-A-G is described in ClinVar as Benign. ClinVar VariationId is 674076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 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.4396-25A>G		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.4396-25A>G		intron	N/A	ENSP00000348965.4	Q14204
	DYNC1H1	ENST00000681574.1		c.4396-25A>G		intron	N/A	ENSP00000505523.1	A0A7P0T9C4
	DYNC1H1	ENST00000679720.1		c.4396-25A>G		intron	N/A	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31491 AN: 151914 Hom.: 4399 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.173 AC: 43525 AN: 251418 AF XY: 0.168

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.288

Gnomad FIN exome AF: 0.0964

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.134 AC: 195251 AN: 1461744 Hom.: 15947 Cov.: 34 AF XY: 0.135 AC XY: 98311 AN XY: 727194

African (AFR) AF: 0.399 AC: 13371 AN: 33472

American (AMR) AF: 0.211 AC: 9423 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4609 AN: 26136

East Asian (EAS) AF: 0.274 AC: 10883 AN: 39698

South Asian (SAS) AF: 0.226 AC: 19478 AN: 86252

European-Finnish (FIN) AF: 0.102 AC: 5429 AN: 53420

Middle Eastern (MID) AF: 0.176 AC: 1018 AN: 5768

European-Non Finnish (NFE) AF: 0.110 AC: 121779 AN: 1111882

Other (OTH) AF: 0.153 AC: 9261 AN: 60392

GnomAD4 genome AF: 0.208 AC: 31554 AN: 152030 Hom.: 4411 Cov.: 32 AF XY: 0.206 AC XY: 15310 AN XY: 74298

African (AFR) AF: 0.390 AC: 16178 AN: 41440

American (AMR) AF: 0.196 AC: 2988 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 587 AN: 3470

East Asian (EAS) AF: 0.275 AC: 1423 AN: 5172

South Asian (SAS) AF: 0.238 AC: 1144 AN: 4808

European-Finnish (FIN) AF: 0.102 AC: 1078 AN: 10586

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7633 AN: 67972

Other (OTH) AF: 0.202 AC: 427 AN: 2112

Alfa AF: 0.153 Hom.: 1059

Bravo AF: 0.222

Asia WGS AF: 0.262 AC: 909 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2O (1)
-	-	1	Intellectual disability, autosomal dominant 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0070
DANN	Benign	0.46
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2251644;

hg19: chr14-102467847;

COSMIC: COSV64135217;