ENST00000307641.9:c.-246C>G

Variant names:

• chr17-42017395-C-G
• rs782649180
• ENST00000307641.9:c.-246C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000307641.9(NKIRAS2):​c.-246C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000261 in 1,456,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: NKIRAS2 ENST00000307641.9 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.51
• Publications: 3 publications found

Genes affected

NKIRAS2 (HGNC:17898): (NFKB inhibitor interacting Ras like 2) Predicted to enable GTPase activating protein binding activity. Predicted to be involved in I-kappaB kinase/NF-kappaB signaling. Predicted to act upstream of or within several processes, including Ral protein signal transduction; regulation of signal transduction; and surfactant homeostasis. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DNAJC7 (HGNC:12392): (DnaJ heat shock protein family (Hsp40) member C7) This gene encodes a member of the DNAJ heat shock protein 40 family of proteins that is characterized by two N-terminal tetratricopeptide repeat domains and a C-terminal DNAJ domain. This protein binds the chaperone proteins heat shock proteins 70 and 90 in an ATP-dependent manner and may function as a co-chaperone. Pseudogenes of this gene are found on chromosomes 1 and 6. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2009]

DNAJC7 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.328247).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000307641.9. 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
	DNAJC7	NM_003315.4	MANE Select	c.22G>C	p.Asp8His	missense	Exon 1 of 14	NP_003306.3	Q99615-1
	DNAJC7	NR_029431.2		n.45G>C		non_coding_transcript_exon	Exon 1 of 13
	DNAJC7	NM_001144766.3		c.-447G>C		upstream_gene	N/A	NP_001138238.1	Q99615-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKIRAS2	ENST00000307641.9	TSL:1	c.-246C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000303580.5	Q9NYR9-1
	DNAJC7	ENST00000457167.9	TSL:1 MANE Select	c.22G>C	p.Asp8His	missense	Exon 1 of 14	ENSP00000406463.2	Q99615-1
	DNAJC7	ENST00000316603.12	TSL:1	c.-58G>C		5_prime_UTR	Exon 1 of 13	ENSP00000313311.7	Q99615-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000204 AC: 5 AN: 244696 AF XY: 0.00000749

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: 0.0000446

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 38 AN: 1456978 Hom.: 0 Cov.: 31 AF XY: 0.0000221 AC XY: 16 AN XY: 725078

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111828

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.41		Loss of disorder (P = 0.0393)
MVP		0.54
MPC		0.78
ClinPred		0.42	T
GERP RS		5.3
PromoterAI		-0.18	Neutral
Varity_R		0.42
gMVP		0.75
Mutation Taster		=67/233	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs782649180; hg19: chr17-40169413;