chr11-103156711-C-T

Variant names:

• chr11-103156711-C-T
• rs74713170
• NM_001080463.2:c.4068C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001080463.2(DYNC2H1):​c.4068C>T​(p.Phe1356Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,613,274 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (70 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (67 hom.)
• Consequence: DYNC2H1 NM_001080463.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.19
• Publications: 3 publications found

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

DYNC2H1 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-103156711-C-T is Benign according to our data. Variant chr11-103156711-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0559 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. 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
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.4068C>T	p.Phe1356Phe	synonymous	Exon 26 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.4068C>T	p.Phe1356Phe	synonymous	Exon 26 of 89	NP_001368.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.4068C>T	p.Phe1356Phe	synonymous	Exon 26 of 90	ENSP00000497174.1
	DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.4068C>T	p.Phe1356Phe	synonymous	Exon 26 of 89	ENSP00000364887.2
	DYNC2H1	ENST00000334267.11	TSL:1	c.2205+22292C>T		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2559 AN: 152112 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.0574

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.00448 AC: 1112 AN: 248002 AF XY: 0.00334

Gnomad AFR exome AF: 0.0600

Gnomad AMR exome AF: 0.00259

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00145

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000329

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00184 AC: 2694 AN: 1461044 Hom.: 67 Cov.: 32 AF XY: 0.00164 AC XY: 1192 AN XY: 726776

African (AFR) AF: 0.0575 AC: 1922 AN: 33432

American (AMR) AF: 0.00345 AC: 154 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39664

South Asian (SAS) AF: 0.000593 AC: 51 AN: 86072

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53368

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5766

European-Non Finnish (NFE) AF: 0.000243 AC: 270 AN: 1111644

Other (OTH) AF: 0.00401 AC: 242 AN: 60354

GnomAD4 genome AF: 0.0170 AC: 2585 AN: 152230 Hom.: 70 Cov.: 32 AF XY: 0.0160 AC XY: 1193 AN XY: 74432

African (AFR) AF: 0.0578 AC: 2403 AN: 41548

American (AMR) AF: 0.00805 AC: 123 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5192

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67982

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.00519 Hom.: 9

Bravo AF: 0.0189

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Asphyxiating thoracic dystrophy 3 (2)
-	-	2	Jeune thoracic dystrophy (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.68
PhyloP100		2.2
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: rs74713170; hg19: chr11-103027440; COSMIC: COSV62089880;