rs4906172

Variant names:

• chr14-101988596-C-A
• rs4906172
• NM_001376.5:c.2719-107C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-101988596-C-A
• chr14-101988596-C-G
• chr14-101988596-C-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.2719-107C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,447,390 control chromosomes in the GnomAD database, including 48,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (13150 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34881 hom.)
• Consequence: DYNC1H1 NM_001376.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.514
• Publications: 15 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-101988596-C-A is Benign according to our data. Variant chr14-101988596-C-A is described in ClinVar as [Benign]. Clinvar id is 674054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5	c.2719-107C>A		intron_variant	Intron 9 of 77	ENST00000360184.10	NP_001367.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.2719-107C>A		intron_variant	Intron 9 of 77	1	NM_001376.5	ENSP00000348965.4

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53341 AN: 151988 Hom.: 13106 Cov.: 32

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.346

GnomAD4 exome AF: 0.215 AC: 277904 AN: 1295282 Hom.: 34881 AF XY: 0.214 AC XY: 139140 AN XY: 651042

African (AFR) AF: 0.726 AC: 21872 AN: 30124

American (AMR) AF: 0.277 AC: 11417 AN: 41254

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6015 AN: 24864

East Asian (EAS) AF: 0.274 AC: 10493 AN: 38256

South Asian (SAS) AF: 0.258 AC: 20912 AN: 81098

European-Finnish (FIN) AF: 0.202 AC: 8870 AN: 43908

Middle Eastern (MID) AF: 0.264 AC: 1450 AN: 5486

European-Non Finnish (NFE) AF: 0.188 AC: 183521 AN: 975264

Other (OTH) AF: 0.243 AC: 13354 AN: 55028

GnomAD4 genome AF: 0.351 AC: 53446 AN: 152108 Hom.: 13150 Cov.: 32 AF XY: 0.346 AC XY: 25729 AN XY: 74362

African (AFR) AF: 0.707 AC: 29319 AN: 41476

American (AMR) AF: 0.282 AC: 4316 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3470

East Asian (EAS) AF: 0.277 AC: 1431 AN: 5174

South Asian (SAS) AF: 0.265 AC: 1275 AN: 4820

European-Finnish (FIN) AF: 0.213 AC: 2249 AN: 10574

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13121 AN: 67980

Other (OTH) AF: 0.343 AC: 725 AN: 2114

Alfa AF: 0.245 Hom.: 15378

Bravo AF: 0.372

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.16
DANN	Benign	0.22
PhyloP100		-0.51
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

Other links and lift over

dbSNP: rs4906172; hg19: chr14-102454933;