2-224379725-T-G

Variant names:

• chr2-224379725-T-G
• rs1250048767
• NM_001122779.2:c.1216A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122779.2(FAM124B):​c.1216A>C​(p.Lys406Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K406E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM124B NM_001122779.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.442
• Publications: 0 publications found

Genes affected

FAM124B (HGNC:26224): (family with sequence similarity 124 member B) Located in mitochondrion and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.075969905).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122779.2. 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
	FAM124B	NM_001122779.2	MANE Select	c.1216A>C	p.Lys406Gln	missense	Exon 2 of 2	NP_001116251.1	Q9H5Z6-1
	FAM124B	NM_024785.3		c.*522A>C		3_prime_UTR	Exon 3 of 3	NP_079061.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM124B	ENST00000409685.4	TSL:2 MANE Select	c.1216A>C	p.Lys406Gln	missense	Exon 2 of 2	ENSP00000386895.3	Q9H5Z6-1
	FAM124B	ENST00000389874.3	TSL:1	c.*522A>C		3_prime_UTR	Exon 3 of 3	ENSP00000374524.3	Q9H5Z6-2
	FAM124B	ENST00000951903.1		c.1210A>C	p.Lys404Gln	missense	Exon 2 of 2	ENSP00000621962.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399424 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 690220

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078976

Other (OTH) AF: 0.00 AC: 0 AN: 58010

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.34
DANN	Benign	0.80
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.44
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.062
Sift	Benign	0.36	T
Sift4G	Benign	0.62	T
Polyphen		0.66	P
Vest4		0.047
MutPred		0.16		Loss of ubiquitination at K406 (P = 0.0092)
MVP		0.54
MPC		0.13
ClinPred		0.17	T
GERP RS		-2.7
Varity_R		0.059
gMVP		0.34
Mutation Taster		=92/8	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: rs1250048767; hg19: chr2-225244442;