14-101991691-C-T

Position:

• chr14-101991691-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001376.5(DYNC1H1):​c.3015+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,613,702 control chromosomes in the GnomAD database, including 9,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (3138 hom., cov: 32)
  • Exomes 𝑓: 0.078 (6320 hom.)
• Consequence: DYNC1H1 NM_001376.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.11

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-101991691-C-T is Benign according to our data. Variant chr14-101991691-C-T is described in ClinVar as [Benign]. Clinvar id is 137182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101991691-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC1H1	NM_001376.5	c.3015+18C>T		intron_variant		ENST00000360184.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.3015+18C>T		intron_variant		1	NM_001376.5	P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23331 AN: 151978 Hom.: 3130 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0833

Gnomad ASJ AF: 0.0793

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0566

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0722

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.0865 AC: 21722 AN: 251236 Hom.: 1761 AF XY: 0.0808 AC XY: 10977 AN XY: 135838

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.0542

Gnomad ASJ exome AF: 0.0716

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0661

Gnomad FIN exome AF: 0.0922

Gnomad NFE exome AF: 0.0748

Gnomad OTH exome AF: 0.0831

GnomAD4 exome AF: 0.0780 AC: 114066 AN: 1461606 Hom.: 6320 Cov.: 33 AF XY: 0.0768 AC XY: 55857 AN XY: 727122

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.0579

Gnomad4 ASJ exome AF: 0.0723

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0661

Gnomad4 FIN exome AF: 0.0939

Gnomad4 NFE exome AF: 0.0722

Gnomad4 OTH exome AF: 0.0889

GnomAD4 genome AF: 0.154 AC: 23375 AN: 152096 Hom.: 3138 Cov.: 32 AF XY: 0.151 AC XY: 11195 AN XY: 74366

Gnomad4 AFR AF: 0.366

Gnomad4 AMR AF: 0.0831

Gnomad4 ASJ AF: 0.0793

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0567

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.0722

Gnomad4 OTH AF: 0.139

Alfa AF: 0.0909 Hom.: 352

Bravo AF: 0.162

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2013	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. -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease axonal type 2O Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.062
DANN	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2749894; hg19: chr14-102458028;