rs10224611

Variant names:

• chr7-6043275-C-T
• rs10224611
• NM_014413.4:c.731-282G>A

Variant summary

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

The NM_014413.4(EIF2AK1):​c.731-282G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,010 control chromosomes in the GnomAD database, including 3,988 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 0.20 (3988 hom., cov: 31)
• Consequence: EIF2AK1 NM_014413.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.774
• Publications: 3 publications found

Genes affected

EIF2AK1 (HGNC:24921): (eukaryotic translation initiation factor 2 alpha kinase 1) The protein encoded by this gene acts at the level of translation initiation to downregulate protein synthesis in response to stress. The encoded protein is a kinase that can be inactivated by hemin. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

EIF2AK1 Gene-Disease associations (from GenCC):

• leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK1	NM_014413.4	c.731-282G>A		intron_variant	Intron 7 of 14	ENST00000199389.11	NP_055228.2
EIF2AK1	NM_001134335.2	c.731-285G>A		intron_variant	Intron 7 of 14		NP_001127807.1
EIF2AK1	XM_047420200.1	c.107-282G>A		intron_variant	Intron 3 of 10		XP_047276156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK1	ENST00000199389.11	c.731-282G>A		intron_variant	Intron 7 of 14	1	NM_014413.4	ENSP00000199389.6
EIF2AK1	ENST00000470168.1	n.468-282G>A		intron_variant	Intron 2 of 3	1
EIF2AK1	ENST00000474029.5	n.305-282G>A		intron_variant	Intron 2 of 3	3
EIF2AK1	ENST00000495565.5	n.308-282G>A		intron_variant	Intron 3 of 4	3

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30694 AN: 151894 Hom.: 3980 Cov.: 31

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.0856

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.181

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

GnomAD4 genome AF: 0.202 AC: 30726 AN: 152010 Hom.: 3988 Cov.: 31 AF XY: 0.201 AC XY: 14920 AN XY: 74318

African (AFR) AF: 0.370 AC: 15316 AN: 41434

American (AMR) AF: 0.166 AC: 2532 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0856 AC: 297 AN: 3470

East Asian (EAS) AF: 0.121 AC: 625 AN: 5156

South Asian (SAS) AF: 0.134 AC: 647 AN: 4820

European-Finnish (FIN) AF: 0.147 AC: 1561 AN: 10588

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9275 AN: 67962

Other (OTH) AF: 0.182 AC: 385 AN: 2114

Alfa AF: 0.176 Hom.: 663

Bravo AF: 0.210

Asia WGS AF: 0.147 AC: 511 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		0.77
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: rs10224611; hg19: chr7-6082906;