17-42021602-G-T

Variant names:

• chr17-42021602-G-T
• rs781912559
• NM_017595.6:c.25G>T

Variant summary

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

The NM_017595.6(NKIRAS2):​c.25G>T​(p.Val9Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V9M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKIRAS2 NM_017595.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.95
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017595.6. 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
	NKIRAS2	NM_017595.6	MANE Select	c.25G>T	p.Val9Leu	missense	Exon 2 of 4	NP_060065.2
	NKIRAS2	NM_001001349.2		c.25G>T	p.Val9Leu	missense	Exon 2 of 4	NP_001001349.1	Q9NYR9-1
	NKIRAS2	NM_001144927.2		c.25G>T	p.Val9Leu	missense	Exon 2 of 4	NP_001138399.1	Q9NYR9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKIRAS2	ENST00000393885.9	TSL:1 MANE Select	c.25G>T	p.Val9Leu	missense	Exon 2 of 4	ENSP00000377463.3	Q9NYR9-1
	NKIRAS2	ENST00000307641.9	TSL:1	c.25G>T	p.Val9Leu	missense	Exon 2 of 4	ENSP00000303580.5	Q9NYR9-1
	NKIRAS2	ENST00000393879.3	TSL:1	n.1187G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.0060	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.57
Sift	Benign	0.056	T
Sift4G	Uncertain	0.015	D
Polyphen		0.97	D
Vest4		0.66
MutPred		0.60		Gain of sheet (P = 0.0827)
MVP		0.72
MPC		0.62
ClinPred		0.87	D
GERP RS		5.7
PromoterAI		0.0098	Neutral
Varity_R		0.44
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs781912559; hg19: chr17-40173620;