14-102050093-G-C

Variant names:

• chr14-102050093-G-C
• rs138571942
• NM_001376.5:c.13707G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001376.5(DYNC1H1):​c.13707G>C​(p.Thr4569Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000706 in 1,416,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T4569T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: DYNC1H1 NM_001376.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.589
• Publications: 1 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: Genomics England PanelApp, Orphanet, G2P
• intellectual disability, autosomal dominant 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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

ENSG00000293472 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 14-102050093-G-C is Benign according to our data. Variant chr14-102050093-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 312667.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000706 (10/1416844) while in subpopulation MID AF = 0.00105 (6/5736). AF 95% confidence interval is 0.000455. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 10 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.13707G>C	p.Thr4569Thr	synonymous	Exon 77 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.13707G>C	p.Thr4569Thr	synonymous	Exon 77 of 78	ENSP00000348965.4	Q14204
	DYNC1H1	ENST00000681574.1		c.13707G>C	p.Thr4569Thr	synonymous	Exon 77 of 77	ENSP00000505523.1	A0A7P0T9C4
	DYNC1H1	ENST00000679720.1		c.13707G>C	p.Thr4569Thr	synonymous	Exon 77 of 78	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251412 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00000706 AC: 10 AN: 1416844 Hom.: 0 Cov.: 32 AF XY: 0.00000851 AC XY: 6 AN XY: 704910

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 39086

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25570

East Asian (EAS) AF: 0.00 AC: 0 AN: 23122

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48972

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5736

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098726

Other (OTH) AF: 0.0000173 AC: 1 AN: 57922

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000473 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Charcot-Marie-Tooth disease axonal type 2O (2)
-	1	-	Autosomal dominant cerebellar ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.2
DANN	Benign	0.78
PhyloP100		-0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs138571942; hg19: chr14-102516430;