10-68431874-C-T

Variant names:

• chr10-68431874-C-T
• rs61855090
• NM_001080449.3:c.1971G>A

Variant summary

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

The NM_001080449.3(DNA2):​c.1971G>A​(p.Thr657Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.045 in 1,608,528 control chromosomes in the GnomAD database, including 2,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (154 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1858 hom.)
• Consequence: DNA2 NM_001080449.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0640
• Publications: 6 publications found

Genes affected

DNA2 (HGNC:2939): (DNA replication helicase/nuclease 2) This gene encodes a member of the DNA2/NAM7 helicase family. The encoded protein is a conserved helicase/nuclease involved in the maintenance of mitochondrial and nuclear DNA stability. Mutations in this gene are associated with autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) and Seckel syndrome 8. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

DNA2 Gene-Disease associations (from GenCC):

• mitochondrial DNA deletion syndrome with progressive myopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Seckel syndrome 8

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 10-68431874-C-T is Benign according to our data. Variant chr10-68431874-C-T is described in ClinVar as Benign. ClinVar VariationId is 257342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.064 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0597 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080449.3. 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
	DNA2	NM_001080449.3	MANE Select	c.1971G>A	p.Thr657Thr	synonymous	Exon 13 of 21	NP_001073918.2	P51530-1
	DNA2	NR_102264.2		n.2060G>A		non_coding_transcript_exon	Exon 14 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNA2	ENST00000358410.8	TSL:1 MANE Select	c.1971G>A	p.Thr657Thr	synonymous	Exon 13 of 21	ENSP00000351185.3	P51530-1
	DNA2	ENST00000551118.6	TSL:5	c.1971G>A	p.Thr657Thr	synonymous	Exon 13 of 17	ENSP00000450393.3	F8VR31
	DNA2	ENST00000936797.1		c.2064G>A	p.Thr688Thr	synonymous	Exon 14 of 22	ENSP00000606856.1

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 5724 AN: 152118 Hom.: 155 Cov.: 32

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0413

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0509

Gnomad FIN AF: 0.0594

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0474

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0451 AC: 11189 AN: 247872 AF XY: 0.0470

Gnomad AFR exome AF: 0.00582

Gnomad AMR exome AF: 0.0273

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.000279

Gnomad FIN exome AF: 0.0610

Gnomad NFE exome AF: 0.0475

Gnomad OTH exome AF: 0.0562

GnomAD4 exome AF: 0.0457 AC: 66586 AN: 1456292 Hom.: 1858 Cov.: 29 AF XY: 0.0466 AC XY: 33758 AN XY: 724716

African (AFR) AF: 0.00630 AC: 210 AN: 33334

American (AMR) AF: 0.0283 AC: 1257 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 3896 AN: 26058

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39652

South Asian (SAS) AF: 0.0550 AC: 4722 AN: 85818

European-Finnish (FIN) AF: 0.0622 AC: 3321 AN: 53378

Middle Eastern (MID) AF: 0.0651 AC: 374 AN: 5746

European-Non Finnish (NFE) AF: 0.0451 AC: 49920 AN: 1107616

Other (OTH) AF: 0.0478 AC: 2878 AN: 60224

GnomAD4 genome AF: 0.0376 AC: 5724 AN: 152236 Hom.: 154 Cov.: 32 AF XY: 0.0380 AC XY: 2826 AN XY: 74434

African (AFR) AF: 0.00763 AC: 317 AN: 41544

American (AMR) AF: 0.0411 AC: 629 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 514 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0516 AC: 249 AN: 4826

European-Finnish (FIN) AF: 0.0594 AC: 629 AN: 10596

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0474 AC: 3224 AN: 68020

Other (OTH) AF: 0.0521 AC: 110 AN: 2112

Alfa AF: 0.0453 Hom.: 157

Bravo AF: 0.0340

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.0501

EpiControl AF: 0.0503

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	2.3
DANN	Benign	0.80
PhyloP100		0.064
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61855090; hg19: chr10-70191631; COSMIC: COSV64428569; COSMIC: COSV64428569;