21-21280658-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004540.5(NCAM2):c.130+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,521,412 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (38 hom.)
• Consequence: NCAM2 NM_004540.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.006744
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.08

Genes affected

NCAM2 (HGNC:7657): (neural cell adhesion molecule 2) The protein encoded by this gene belongs to the immunoglobulin superfamily. It is a type I membrane protein and may function in selective fasciculation and zone-to-zone projection of the primary olfactory axons. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 21-21280658-T-C is Benign according to our data. Variant chr21-21280658-T-C is described in ClinVar as [Benign]. Clinvar id is 3044809.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00316 (482/152314) while in subpopulation EAS AF= 0.023 (119/5168). AF 95% confidence interval is 0.0197. There are 5 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCAM2	NM_004540.5	c.130+6T>C		splice_donor_region_variant, intron_variant		ENST00000400546.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCAM2	ENST00000400546.6	c.130+6T>C		splice_donor_region_variant, intron_variant		1	NM_004540.5	P1
NCAM2	ENST00000284894.8	c.76+6T>C		splice_donor_region_variant, intron_variant		5
NCAM2	ENST00000486367.1	n.145+6T>C		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 483 AN: 152196 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0230

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00482 AC: 928 AN: 192498 Hom.: 21 AF XY: 0.00463 AC XY: 490 AN XY: 105740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000125

Gnomad EAS exome AF: 0.0268

Gnomad SAS exome AF: 0.000870

Gnomad FIN exome AF: 0.0262

Gnomad NFE exome AF: 0.000507

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00177 AC: 2419 AN: 1369098 Hom.: 38 Cov.: 24 AF XY: 0.00169 AC XY: 1149 AN XY: 678454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000413

Gnomad4 EAS exome AF: 0.0286

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.0205

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00316 AC: 482 AN: 152314 Hom.: 5 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74472

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0230

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0287

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000722 Hom.: 0

Bravo AF: 0.00131

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NCAM2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	16
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0067
dbscSNV1_RF	Benign	0.16
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

Publications

LitVar

Other links and lift over

dbSNP: rs75625065; hg19: chr21-22652978;