chr14-102030015-C-A

Variant names:

• chr14-102030015-C-A
• rs2253998
• NM_001376.5:c.9762+77C>A

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.9762+77C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,610,468 control chromosomes in the GnomAD database, including 49,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11694 hom., cov: 31)
  • Exomes 𝑓: 0.21 (37312 hom.)
• Consequence: DYNC1H1 NM_001376.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.04
• Publications: 7 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=-0.88).
• BP6: Variant 14-102030015-C-A is Benign according to our data. Variant chr14-102030015-C-A is described in ClinVar as Benign. ClinVar VariationId is 674055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.655 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	NM_001376.5	MANE Select	c.9762+77C>A		intron	N/A	NP_001367.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	ENST00000360184.10	TSL:1 MANE Select	c.9762+77C>A		intron	N/A	ENSP00000348965.4
	DYNC1H1	ENST00000681574.1		c.9762+77C>A		intron	N/A	ENSP00000505523.1
	DYNC1H1	ENST00000679720.1		c.9762+77C>A		intron	N/A	ENSP00000505938.1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50922 AN: 151568 Hom.: 11658 Cov.: 31

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.0960

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.333

GnomAD4 exome AF: 0.211 AC: 307760 AN: 1458782 Hom.: 37312 Cov.: 33 AF XY: 0.211 AC XY: 152760 AN XY: 725654

African (AFR) AF: 0.686 AC: 22939 AN: 33446

American (AMR) AF: 0.270 AC: 11975 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6327 AN: 26118

East Asian (EAS) AF: 0.272 AC: 10801 AN: 39640

South Asian (SAS) AF: 0.256 AC: 21914 AN: 85610

European-Finnish (FIN) AF: 0.202 AC: 10726 AN: 53212

Middle Eastern (MID) AF: 0.255 AC: 1466 AN: 5746

European-Non Finnish (NFE) AF: 0.187 AC: 207343 AN: 1110288

Other (OTH) AF: 0.237 AC: 14269 AN: 60312

GnomAD4 genome AF: 0.336 AC: 51019 AN: 151686 Hom.: 11694 Cov.: 31 AF XY: 0.331 AC XY: 24542 AN XY: 74108

African (AFR) AF: 0.662 AC: 27324 AN: 41306

American (AMR) AF: 0.274 AC: 4175 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 832 AN: 3458

East Asian (EAS) AF: 0.274 AC: 1406 AN: 5140

South Asian (SAS) AF: 0.262 AC: 1261 AN: 4810

European-Finnish (FIN) AF: 0.211 AC: 2219 AN: 10510

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.190 AC: 12937 AN: 67926

Other (OTH) AF: 0.330 AC: 696 AN: 2108

Alfa AF: 0.234 Hom.: 3100

Bravo AF: 0.356

Asia WGS AF: 0.283 AC: 983 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.34
PhyloP100		-1.0
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: rs2253998; hg19: chr14-102496352; COSMIC: COSV64135223; COSMIC: COSV64135223;