rs7913176

Variant names:

• chr10-113884281-G-A
• rs7913176
• NM_198514.4:c.940G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_198514.4(NHLRC2):​c.940G>A​(p.Val314Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,608,448 control chromosomes in the GnomAD database, including 63,487 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.25 (5162 hom., cov: 32)
  • Exomes 𝑓: 0.28 (58325 hom.)
• Consequence: NHLRC2 NM_198514.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.65
• Publications: 33 publications found

Genes affected

NHLRC2 (HGNC:24731): (NHL repeat containing 2) Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

NHLRC2 Gene-Disease associations (from GenCC):

• fibrosis, neurodegeneration, and cerebral angiomatosis

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014792085).
• BP6: Variant 10-113884281-G-A is Benign according to our data. Variant chr10-113884281-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059194.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198514.4. 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
	NHLRC2	NM_198514.4	MANE Select	c.940G>A	p.Val314Ile	missense	Exon 5 of 11	NP_940916.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC2	ENST00000369301.3	TSL:2 MANE Select	c.940G>A	p.Val314Ile	missense	Exon 5 of 11	ENSP00000358307.3	Q8NBF2-1
	NHLRC2	ENST00000918088.1		c.940G>A	p.Val314Ile	missense	Exon 5 of 11	ENSP00000588147.1
	NHLRC2	ENST00000866165.1		c.787G>A	p.Val263Ile	missense	Exon 4 of 10	ENSP00000536224.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37925 AN: 151572 Hom.: 5157 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.226

GnomAD2 exomes AF: 0.276 AC: 69339 AN: 250812 AF XY: 0.273

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.330

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.291

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.279 AC: 406600 AN: 1456756 Hom.: 58325 Cov.: 30 AF XY: 0.277 AC XY: 201023 AN XY: 724860

African (AFR) AF: 0.139 AC: 4647 AN: 33356

American (AMR) AF: 0.266 AC: 11894 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5803 AN: 25996

East Asian (EAS) AF: 0.285 AC: 11252 AN: 39522

South Asian (SAS) AF: 0.203 AC: 17453 AN: 86078

European-Finnish (FIN) AF: 0.386 AC: 20584 AN: 53268

Middle Eastern (MID) AF: 0.189 AC: 1083 AN: 5740

European-Non Finnish (NFE) AF: 0.287 AC: 317986 AN: 1108008

Other (OTH) AF: 0.264 AC: 15898 AN: 60130

GnomAD4 genome AF: 0.250 AC: 37937 AN: 151692 Hom.: 5162 Cov.: 32 AF XY: 0.253 AC XY: 18745 AN XY: 74144

African (AFR) AF: 0.152 AC: 6289 AN: 41500

American (AMR) AF: 0.254 AC: 3863 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 832 AN: 3462

East Asian (EAS) AF: 0.329 AC: 1697 AN: 5160

South Asian (SAS) AF: 0.200 AC: 964 AN: 4824

European-Finnish (FIN) AF: 0.392 AC: 4134 AN: 10536

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19403 AN: 67676

Other (OTH) AF: 0.223 AC: 471 AN: 2108

Alfa AF: 0.272 Hom.: 26727

Bravo AF: 0.238

TwinsUK AF: 0.295 AC: 1095

ALSPAC AF: 0.294 AC: 1134

ESP6500AA AF: 0.155 AC: 684

ESP6500EA AF: 0.282 AC: 2422

ExAC AF: 0.272 AC: 32986

Asia WGS AF: 0.252 AC: 875 AN: 3478

EpiCase AF: 0.271

EpiControl AF: 0.265

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NHLRC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-0.074
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.25	N
REVEL	Uncertain	0.30
Sift	Benign	0.43	T
Sift4G	Benign	0.64	T
Polyphen		0.55	P
Vest4		0.047
MPC		0.11
ClinPred		0.014	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.082
gMVP		0.24
Mutation Taster		=90/10	polymorphism (auto)

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: rs7913176; hg19: chr10-115644040; COSMIC: COSV65174376;