NM_001134232.2:c.441+1977C>T

Variant names:

• chr7-12226362-C-T
• rs6966915
• NM_001134232.2:c.441+1977C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134232.2(TMEM106B):​c.441+1977C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 151,932 control chromosomes in the GnomAD database, including 20,207 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (20207 hom., cov: 32)
• Consequence: TMEM106B NM_001134232.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.429
• Publications: 32 publications found

Genes affected

TMEM106B (HGNC:22407): (transmembrane protein 106B) Enables ATPase binding activity. Involved in dendrite morphogenesis and lysosome localization. Located in endosome and lysosomal membrane. Implicated in hypomyelinating leukodystrophy. [provided by Alliance of Genome Resources, Apr 2022]

TMEM106B Gene-Disease associations (from GenCC):

• leukodystrophy, hypomyelinating, 16

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134232.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM106B	NM_001134232.2	MANE Select	c.441+1977C>T		intron	N/A	NP_001127704.1
	TMEM106B	NM_018374.4		c.441+1977C>T		intron	N/A	NP_060844.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM106B	ENST00000396668.8	TSL:1 MANE Select	c.441+1977C>T		intron	N/A	ENSP00000379902.3
	TMEM106B	ENST00000396667.7	TSL:1	c.441+1977C>T		intron	N/A	ENSP00000379901.2
	TMEM106B	ENST00000420833.5	TSL:1	n.*327+1977C>T		intron	N/A	ENSP00000391016.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76221 AN: 151814 Hom.: 20181 Cov.: 32

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.474

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.502 AC: 76297 AN: 151932 Hom.: 20207 Cov.: 32 AF XY: 0.504 AC XY: 37431 AN XY: 74266

African (AFR) AF: 0.655 AC: 27145 AN: 41464

American (AMR) AF: 0.541 AC: 8263 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1527 AN: 3470

East Asian (EAS) AF: 0.644 AC: 3332 AN: 5176

South Asian (SAS) AF: 0.612 AC: 2944 AN: 4814

European-Finnish (FIN) AF: 0.334 AC: 3519 AN: 10540

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.413 AC: 28025 AN: 67892

Other (OTH) AF: 0.474 AC: 1001 AN: 2112

Alfa AF: 0.440 Hom.: 63452

Bravo AF: 0.524

Asia WGS AF: 0.594 AC: 2066 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.80
DANN	Benign	0.36
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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: rs6966915; hg19: chr7-12265988;