rs72978714

Variant names:

• chr3-136946128-G-C
• rs72978714
• NM_001291999.2:c.772G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001291999.2(NCK1):​c.772G>C​(p.Gly258Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,613,712 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (76 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (95 hom.)
• Consequence: NCK1 NM_001291999.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.995
• Publications: 4 publications found

Genes affected

NCK1 (HGNC:7664): (NCK adaptor protein 1) The protein encoded by this gene is one of the signaling and transforming proteins containing Src homology 2 and 3 (SH2 and SH3) domains. It is located in the cytoplasm and is an adaptor protein involved in transducing signals from receptor tyrosine kinases to downstream signal recipients such as RAS. Alternatively spliced transcript variants encoding different isoforms have been found. [provided by RefSeq, Jun 2010]

IL20RB-AS1 (HGNC:40298): (IL20RB antisense RNA 1)

IL20RB (HGNC:6004): (interleukin 20 receptor subunit beta) IL20RB and IL20RA (MIM 605620) form a heterodimeric receptor for interleukin-20 (IL20; MIM 605619) (Blumberg et al., 2001 [PubMed 11163236]).[supplied by OMIM, Feb 2009]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.027).
• BP6: Variant 3-136946128-G-C is Benign according to our data. Variant chr3-136946128-G-C is described in ClinVar as Benign. ClinVar VariationId is 775909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291999.2. 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
	NCK1	NM_001291999.2	MANE Select	c.772G>C	p.Gly258Arg	missense	Exon 3 of 4	NP_001278928.1	P16333-1
	NCK1	NM_006153.6		c.772G>C	p.Gly258Arg	missense	Exon 3 of 4	NP_006144.1	P16333-1
	NCK1	NM_001190796.3		c.580G>C	p.Gly194Arg	missense	Exon 2 of 3	NP_001177725.1	P16333-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCK1	ENST00000481752.6	TSL:5 MANE Select	c.772G>C	p.Gly258Arg	missense	Exon 3 of 4	ENSP00000417273.1	P16333-1
	NCK1	ENST00000288986.6	TSL:1	c.772G>C	p.Gly258Arg	missense	Exon 3 of 4	ENSP00000288986.2	P16333-1
	NCK1	ENST00000951211.1		c.955G>C	p.Gly319Arg	missense	Exon 4 of 5	ENSP00000621270.1

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2937 AN: 151728 Hom.: 76 Cov.: 31

Gnomad AFR AF: 0.0675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00737

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00525 AC: 1321 AN: 251408 AF XY: 0.00373

Gnomad AFR exome AF: 0.0701

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00194 AC: 2832 AN: 1461866 Hom.: 95 Cov.: 31 AF XY: 0.00169 AC XY: 1228 AN XY: 727230

African (AFR) AF: 0.0683 AC: 2286 AN: 33478

American (AMR) AF: 0.00440 AC: 197 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5766

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111996

Other (OTH) AF: 0.00421 AC: 254 AN: 60396

GnomAD4 genome AF: 0.0194 AC: 2940 AN: 151846 Hom.: 76 Cov.: 31 AF XY: 0.0185 AC XY: 1373 AN XY: 74222

African (AFR) AF: 0.0674 AC: 2789 AN: 41386

American (AMR) AF: 0.00736 AC: 112 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67972

Other (OTH) AF: 0.0119 AC: 25 AN: 2102

Alfa AF: 0.00310 Hom.: 13

Bravo AF: 0.0225

ESP6500AA AF: 0.0604 AC: 266

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00675 AC: 820

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.84
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		0.99
ClinPred		0.0095	T
GERP RS		4.3
Varity_R		0.045
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72978714; hg19: chr3-136664970;