14-69209775-T-C

Variant names:

• chr14-69209775-T-C
• rs1313773946
• NM_001193360.2:c.305T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001193360.2(EXD2):​c.305T>C​(p.Phe102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000198 in 1,515,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: EXD2 NM_001193360.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• Publications: 0 publications found

Genes affected

EXD2 (HGNC:20217): (exonuclease 3'-5' domain containing 2) Enables 3'-5' exonuclease activity; metal ion binding activity; and protein homodimerization activity. Involved in nucleic acid metabolic process. Located in intermediate filament cytoskeleton; mitochondrial outer membrane; and site of DNA damage. [provided by Alliance of Genome Resources, Apr 2022]

GALNT16-AS1 (HGNC:55435): (GALNT16 and EXD2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14026761).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193360.2. 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
	EXD2	NM_001193360.2	MANE Select	c.305T>C	p.Phe102Ser	missense	Exon 3 of 10	NP_001180289.1	Q9NVH0-1
	EXD2	NM_001193361.2		c.305T>C	p.Phe102Ser	missense	Exon 2 of 9	NP_001180290.1	Q9NVH0-1
	EXD2	NM_001193362.2		c.305T>C	p.Phe102Ser	missense	Exon 3 of 10	NP_001180291.1	Q9NVH0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXD2	ENST00000685843.1	MANE Select	c.305T>C	p.Phe102Ser	missense	Exon 3 of 10	ENSP00000510642.1	Q9NVH0-1
	EXD2	ENST00000409018.7	TSL:1	c.305T>C	p.Phe102Ser	missense	Exon 2 of 9	ENSP00000387331.3	Q9NVH0-1
	EXD2	ENST00000413191.1	TSL:1	c.-161T>C		5_prime_UTR	Exon 3 of 6	ENSP00000409089.1	C9JLF4

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151802 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 123688 AF XY: 0.00

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: 0.00000147 AC: 2 AN: 1363244 Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1 AN XY: 669076

African (AFR) AF: 0.00 AC: 0 AN: 30396

American (AMR) AF: 0.00 AC: 0 AN: 29256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23410

East Asian (EAS) AF: 0.0000570 AC: 2 AN: 35082

South Asian (SAS) AF: 0.00 AC: 0 AN: 74494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061230

Other (OTH) AF: 0.00 AC: 0 AN: 56328

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151802 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41294

American (AMR) AF: 0.00 AC: 0 AN: 15206

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.5
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.13
Sift	Benign	0.18	T
Sift4G	Benign	0.28	T
Vest4		0.22
MutPred		0.50		Gain of disorder (P = 0.0049)
MVP		0.64
MPC		0.26
ClinPred		0.26	T
GERP RS		3.0
Varity_R		0.30
gMVP		0.70
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1313773946; hg19: chr14-69676492;