chr19-3196286-C-T

Variant names:

• chr19-3196286-C-T
• rs187629347
• NM_020170.4:c.615+9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020170.4(NCLN):​c.615+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000654 in 1,534,370 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (8 hom.)
• Consequence: NCLN NM_020170.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.176
• Publications: 1 publications found

Genes affected

NCLN (HGNC:26923): (nicalin) Enables ribosome binding activity. Involved in protein stabilization; regulation of protein complex stability; and regulation of protein-containing complex assembly. Located in endoplasmic reticulum membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-3196286-C-T is Benign according to our data. Variant chr19-3196286-C-T is described in ClinVar as [Benign]. Clinvar id is 770651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00054 (747/1382084) while in subpopulation AMR AF = 0.0193 (676/34950). AF 95% confidence interval is 0.0181. There are 8 homozygotes in GnomAdExome4. There are 319 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCLN	NM_020170.4	c.615+9C>T		intron_variant	Intron 4 of 14	ENST00000246117.9	NP_064555.2
NCLN	NM_001321463.2	c.615+9C>T		intron_variant	Intron 4 of 14		NP_001308392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCLN	ENST00000246117.9	c.615+9C>T		intron_variant	Intron 4 of 14	1	NM_020170.4	ENSP00000246117.3
NCLN	ENST00000590671.5	c.393+9C>T		intron_variant	Intron 4 of 14	2		ENSP00000466678.1
NCLN	ENST00000588428.5	c.279+9C>T		intron_variant	Intron 2 of 8	5		ENSP00000467011.1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 252 AN: 152168 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00296 AC: 452 AN: 152728 AF XY: 0.00219

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0185

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: 0.00140

GnomAD4 exome AF: 0.000540 AC: 747 AN: 1382084 Hom.: 8 Cov.: 29 AF XY: 0.000470 AC XY: 319 AN XY: 679204

African (AFR) AF: 0.000128 AC: 4 AN: 31354

American (AMR) AF: 0.0193 AC: 676 AN: 34950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24786

East Asian (EAS) AF: 0.00 AC: 0 AN: 35278

South Asian (SAS) AF: 0.0000892 AC: 7 AN: 78510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00000657 AC: 7 AN: 1065984

Other (OTH) AF: 0.000928 AC: 53 AN: 57094

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152286 Hom.: 4 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74456

African (AFR) AF: 0.000289 AC: 12 AN: 41540

American (AMR) AF: 0.0152 AC: 232 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.000411 Hom.: 0

Bravo AF: 0.00292

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.8
DANN	Benign	0.86
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs187629347; hg19: chr19-3196284; COSMIC: COSV109418456; COSMIC: COSV109418456;