NM_001376.5:c.161C>A

Variant names:

• chr14-101964852-C-A
• rs772070566
• NM_001376.5:c.161C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6_Moderate BS2

The NM_001376.5(DYNC1H1):​c.161C>A​(p.Ala54Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,445,848 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A54V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: DYNC1H1 NM_001376.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.48
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16998452).
• BP6: Variant 14-101964852-C-A is Benign according to our data. Variant chr14-101964852-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3636108.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 5 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.161C>A	p.Ala54Glu	missense	Exon 1 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.161C>A	p.Ala54Glu	missense	Exon 1 of 78	ENSP00000348965.4	Q14204
	DYNC1H1	ENST00000681574.1		c.161C>A	p.Ala54Glu	missense	Exon 1 of 77	ENSP00000505523.1	A0A7P0T9C4
	DYNC1H1	ENST00000679720.1		c.161C>A	p.Ala54Glu	missense	Exon 1 of 78	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000935 AC: 2 AN: 213952 AF XY: 0.00000852

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: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1445848 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 717862

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

American (AMR) AF: 0.00 AC: 0 AN: 42330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 39240

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5324

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105264

Other (OTH) AF: 0.0000168 AC: 1 AN: 59696

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000837 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.071
Sift	Benign	0.17	T
Polyphen		0.020	B
Vest4		0.34
MutPred		0.18		Gain of solvent accessibility (P = 0.08)
MVP		0.35
MPC		1.4
ClinPred		0.31	T
GERP RS		4.2
PromoterAI		0.066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.68
gMVP		0.60
Mutation Taster		=64/36	polymorphism

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: rs772070566; hg19: chr14-102431189;