rs60156239

Variant names:

• chr8-24955849-G-A
• rs60156239
• NM_006158.5:c.667C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-24955849-G-A
• chr8-24955849-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006158.5(NEFL):​c.667C>T​(p.Leu223Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00656 in 1,610,090 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (50 hom.)
• Consequence: NEFL NM_006158.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 5.68
• Publications: 2 publications found

Genes affected

NEFL (HGNC:7739): (neurofilament light chain) Neurofilaments are type IV intermediate filament heteropolymers composed of light, medium, and heavy chains. Neurofilaments comprise the axoskeleton and they functionally maintain the neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene encodes the light chain neurofilament protein. Mutations in this gene cause Charcot-Marie-Tooth disease types 1F (CMT1F) and 2E (CMT2E), disorders of the peripheral nervous system that are characterized by distinct neuropathies. A pseudogene has been identified on chromosome Y. [provided by RefSeq, Oct 2008]

NEFL Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 1F

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 2E

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 2B5

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000272157 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 8-24955849-G-A is Benign according to our data. Variant chr8-24955849-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 66696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00474 (721/152198) while in subpopulation NFE AF = 0.00691 (470/67992). AF 95% confidence interval is 0.0064. There are 4 homozygotes in GnomAd4. There are 368 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006158.5. 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
	NEFL	NM_006158.5	MANE Select	c.667C>T	p.Leu223Leu	synonymous	Exon 1 of 4	NP_006149.2	P07196

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEFL	ENST00000610854.2	TSL:1 MANE Select	c.667C>T	p.Leu223Leu	synonymous	Exon 1 of 4	ENSP00000482169.2	P07196
	NEFL	ENST00000916556.1		c.667C>T	p.Leu223Leu	synonymous	Exon 1 of 4	ENSP00000586615.1
	ENSG00000272157	ENST00000607735.3	TSL:6	n.159G>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 721 AN: 152078 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00691

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00537 AC: 1322 AN: 246094 AF XY: 0.00532

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.00836

Gnomad OTH exome AF: 0.00348

GnomAD4 exome AF: 0.00675 AC: 9842 AN: 1457892 Hom.: 50 Cov.: 37 AF XY: 0.00643 AC XY: 4664 AN XY: 725470

African (AFR) AF: 0.00111 AC: 37 AN: 33472

American (AMR) AF: 0.000626 AC: 28 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86256

European-Finnish (FIN) AF: 0.0153 AC: 762 AN: 49720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00780 AC: 8672 AN: 1111784

Other (OTH) AF: 0.00499 AC: 301 AN: 60354

GnomAD4 genome AF: 0.00474 AC: 721 AN: 152198 Hom.: 4 Cov.: 32 AF XY: 0.00494 AC XY: 368 AN XY: 74432

African (AFR) AF: 0.00120 AC: 50 AN: 41570

American (AMR) AF: 0.00105 AC: 16 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4798

European-Finnish (FIN) AF: 0.0158 AC: 168 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00691 AC: 470 AN: 67992

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00560 Hom.: 3

Bravo AF: 0.00359

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (7)
-	-	4	not specified (4)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2E (1)
-	-	1	Charcot-Marie-Tooth disease, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		5.7

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: rs60156239; hg19: chr8-24813363; COSMIC: COSV108062319;